Selective estrogen receptor modulators

ABSTRACT

The present invention provides, inter alia, triphenylethylene derivatives, such as, 3-{4-[6-(3-Methoxy-phenyl)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenyl}-acrylic acid, as selective estrogen receptor modulators. Also provided are methods for the treatment and/or prevention of estrogen stimulated diseases in mammals including breast, uterine, ovarian, prostrate and colon cancer, osteoporosis, cardiovascular disease, and benign proliferative disorders, as well as pharmaceutical compositions of the compounds of the present invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the priority benefit of U.S. ProvisionalApplication No. 60/311,466, filed Aug. 11, 2001, the disclosure of whichis incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

[0002] This invention pertains to triphenylethylene derivatives, suchas,3-{4-[6-(3-Methoxy-phenyl)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenyl}-acrylicacid, as selective estrogen receptor modulators. This invention alsoprovides methods for the treatment and/or prevention of estrogenstimulated diseases in mammals including breast, uterine, ovarian,prostrate and colon cancer, osteoporosis, cardiovascular disease, andbenign proliferative disorders, as well as pharmaceutical compositionsof the compounds of the present invention.

BACKGROUND OF THE INVENTION

[0003] Approximately 180,000 women are diagnosed with breast cancer eachyear in the United States. Most of these women are cured of theirdisease by surgery and local radiotherapy. However, nearly 60,000 womengo on to develop metastatic breast cancer each year, and 45,000 of thesepatients eventually die from their malignancies. While metastatic breastcancer is rarely curable, it is treatable with modern pharmaceuticalsthat prolong patient survival and reduce the morbidity associated withmetastatic lesions. Foremost among these therapies are hormonalmanipulations that include selective estrogen receptor modifiers(SERMs). SERMs are small ligands of the estrogen receptor that arecapable of inducing a wide variety of conformational changes in thereceptor and thereby eliciting a variety of distinct biologicalprofiles. SERMs not only affect the growth of breast cancer tissue butalso influence other physiological processes. The most widely used SERMin breast cancer is tamoxifen, which is a partial estrogen receptoragonist/antagonist that produces objective responses in approximately50% of the patients. Unfortunately, 100% of patients who take tamoxifeneventually relapse with tamoxifen-resistant tumors. Approximately 50% ofthe patients that fail tamoxifen treatment will respond to a subsequenthormonal manipulation therapy such as castration, aromatase inhibitors,or other SERMs. The second line therapies for hormonal manipulationtherapy of metastatic breast cancer represent a substantial unmet needbecause no single agent has become the treatment of choice for patientswho fail tamoxifen therapy. The ideal agent would be a medication thatinduces regression of metastatic breast cancer lesions in women who havepreviously responded to tamixofen therapy. The present invention isdirected to novel, highly soluble salt forms of the compound3-[4[(1,2-diphenyl-but-1-enyl)-phenyl]-acrylic acid, which is describedin U.S. Pat. No. 5,681,835, the contents of which are hereinincorporated by reference in their entirety.

[0004] SERMs modulate the proliferation of uterine tissue, skeletal bonedensity, and cardiovascular health, including plasma cholesterol levels.In general, estrogen stimulates breast and endometrial tissueproliferation, enhances bone density, and lowers plasma cholesterol.Many SERMs are bifunctional in that they antagonize some of thesefunctions while stimulating others. For example, tamoxifen, which is apartial agonist/antagonist at the estrogen receptor inhibitsestrogen-induced breast cancer cell proliferation but stimulatesendometrial tissue growth and prevents bone loss. Estrogens are animportant class of steroidal hormones that stimulate the development andmaintenance of fundamental sexual characteristics in humans. In thepast, estrogens have been found useful in the treatment of certainmedical conditions and diseases. For example estradiol, a steroidhormone produced by the ovary, is useful in the treatment ofosteoporosis, cardiovascular disease, premenstrual syndrome, vasomotorsymptoms associated with menopause, atrophic vaginitis, Kraurosisvulvae, female hypogonadism, primary ovarian failure, excessive hairgrowth and prostatic cancer.

[0005] Hormone replacement therapy (HRT) with estrogen has beendetermined to be a clinically effective treatment for osteoporosis inpost-menopausal women. However, less than 15% of eligible women arecurrently prescribed HRT despite clinical trials that have demonstrateda 50% reduction in hip fractures and a 30% reduction in cardiovasculardisease. Non-compliance arises from patient and physician concerns overthe two fold increased risk of endometrial cancer observed with HRTemploying estrogen alone as well as the association between estrogentherapy and breast cancer. Although unproven in the clinic, thissuspected risk for breast cancer has led to HRT being contraindicated ina significant percentage of post-menopausal women. Co-therapy withprogestins has been shown to protect the uterus against cancer whilemaintaining the osteoprotective effects of the estrogen, however theprogestin introduces other side effects such as withdrawal bleeding,breast pain and mood swings.

[0006] In light of the more serious side effects associated withestrogen therapy, including myocardial infarction, thromboembolism,cerebrovascular disease, and endometrial carcinoma, a significant amountof research has been carried out to identify effective nonsteroidalestrogen and antiestrogenic compounds. In general, such compounds may becharacterized as both estrogenic and antiestrogenic because, while theyall bind to the estrogen receptor, they may induce an estrogenic orantiestrogenic effect depending upon the location of the receptor. Inthe past, it has been postulated that the binding of variousnonsteroidal estrogen and antiestrogenic compounds to the estrogenreceptor was due to the presence of a common pharmacophore (shown belowin Scheme A), which was recurrent in the chemical structures of thesecompounds.

[0007] This pharmacophore later became the structural backbone aroundwhich nonsteroidal estrogen and antiestrogenic compounds wereconstructed. Its presence in the constructs of various compounds such ashexestrol, tamoxifen, chroman, triphenylethylene, DES, clomiphene,centchroman, nafoxidene, trioxifene, toremifene, zindoxifene,raloxifene, droloxifene, DABP, TAT-59 and other structurally relatedcompounds has become accepted in the art as the molecular key toestrogen receptor binding specificity.

[0008] Estrogen has also been shown to function as a mitogen inestrogen-receptor (ER) positive breast cancer cells. Thus, treatmentregiments which include antiestrogens, synthetic compounds which opposethe actions of estrogen have been effective clinically in halting ordelaying the progression of the disease (Jordan and Murphy, EndocrineReviews 11:578-610 1990); Parker, Breast Cancer Res. Treat. 26:131-137(1993)). The availability of these synthetic ER modulators andsubsequent dissection of their mechanism(s) of action have provideduseful insights into ER action.

[0009] The human estrogen receptor (ER) is a member of the nuclearreceptor superfamily of transcription factors (Evans, Science240:889-895 (1988)). In the absence of hormone, it resides in thenucleus of target cells in a transcriptionally inactive state. Uponbinding ligand, ER undergoes a conformational change initiating acascade of events leading ultimately to its association with specificregulatory regions within target genes (O'Malley et al., HormoneResearch 47:1-26 (1991)). The ensuing effect on transcription isinfluenced by the cell and promoter context of the DNA-bound receptor(Tora et al. Cell 59:471-487 (1989) (Tasset et al., Cell 62:1177-1181(1990); McDonnell et all Mol. Endocrinol. 9:659-669 (1995); Tzukerman etal. Mol. Endocrinol. 8:21-30 (1994)). It is in this manner that thephysiological ER-agonist, extradiol, exerts its biological activity inthe reproductive, skeletal and cardiovascular systems (Clark and Peck,Female Sex Steroids:Receptors and Function (eds) MonographsSpringer-Verlag, New York (1979); Chow et al., J. Clin. Invest.89:74-78(1992); Eaker et al. Circulation 88:1999-2009 (1993)).

[0010] One of the most studied compounds in this regard is tamoxifen(TAM), (Z)1,2-diphenyl-1-[4-[2-(dimethylamino) ethoxy]phenyl]-1-butene,(Jordan and Murphy, Endocrine Reviews 11:578-610 (1990)), which is atriphenylethylene derivative. Tamoxifen functions as an antagonist inmost ER-positive tumors of the breast and ovum, but displays aparadoxical agonist activity in bone and the cardiovascular system andpartial agonist activity in the uterus (Kedar et al. Lancet343:1318-1321 (1994); Love et al., New Engl. J. Med. 326:852-856 (1992);Love et al., Ann. Intern. Med. 115:860-864 (1991)). Thus, theagonist/antagonist activity of the ER-tamoxifen complex is influenced bycell context. This important observation is in apparent contradiction tolongstanding models that hold that ER only exists in the cell in anactive or an inactive state (Clark and Peck, Female SexSteroids:Receptors and Functions (eds) Monographs on Endocrinology,Springer-Verlag, New York (1979)). It indicates instead that differentligands acting through the same receptor can manifest differentbiologies in different cells. Definition of the mechanism of thisselectivity is likely to advance the understanding of processes such astamoxifen resistance, observed in most ER-containing breast cancers,where abnormalities in ER-signaling are implicated (Tonetti and Jordan,Anti-Cancer Drugs 6:498-507 (1995)).

[0011] Tamoxifen, as well as a structurally similar compound known asraloxifene have been developed for the treatment and/or prevention ofosteoporosis, cardiovascular disease and breast cancer in addition tothe treatment and/or prevention of a variety of other disease states.Both compounds have been shown to exhibit an osteoprotective effect onbone mineral density combined with a positive effect on plasmacholesterol levels and a greatly reduced incidence of breast and uterinecancer. Unfortunately, tamoxifen and raloxifene both have unacceptablelevels of life-threatening side effects such as endometrial cancer andhepatocellular carcinoma.

[0012] The likely mechanism for the cell selective agonist/antagonistactivity of tamoxifen has been determined using an in vitro approach(Tora et al., Cell 59:477487 (1989); Tasset et al., Cell 62:1177-1187(1990); McDonnell et al., Mol. Endocrinol. 9:659-669 (1995); Tzukermanet al., Mol. Endocrinol. 8:21-30 (1994)). Importantly, it has been shownthat tamoxifen induces a conformational change within ER which isdistinct from that induced by estradiol (McDonnell et al., Mol.Endocrinol. 9:659-669 (1995); (Beekman et al., Molecular Endocrinology7:1266-1274 (1993)). Furthermore, determination of the sequences withinER required for transcriptional activity indicate how these specificligand-receptor complexes are differentially recognized by the cellulartranscriptional machinery. Specifically, it has been shown that ERcontains two activation domains, AF-1 (Activation Function-1) and AF-2,which permit its interaction with the transcription apparatus. Therelative contribution of these AFs to overall ER efficacy differs fromcell to cell (Tora et al., Cell 59:477-487 (1989); McDonnell et al.,Mol. Endocrinol. 9@65-9-669 (1995); Tzukerman et al., Mol. Endocrinol.8:21-30 (1994)). Estradiol was determined to function as both an AF-1and an AF-2 agonist, in that it exhibited maximal activity regardless ofwhich AF was dominant in a given cellular environment. Tamoxifen, on theother hand, functions as an AF-2 antagonist, inhibiting ER activity incells where AF-2 is required or is the dominant activator (Tora et al.,Cell 59:477-487 (1989); McDonnell et al., Mol. Endocrinol. 9:659-669(1995); Tzukerman et al., Mol. Endocrinol. 8:21-30 (1994)). Conversely,tamoxifen functions as an agonist when AF-1 alone is required (McDonnellet al., Mol. Endocrinol. 9:659-669 (1995); Tzukerman et al., Mol.Endocrinol. 8:21-30 (1994)). Subsequently, based on their relativeAF-1/AF-2 activity, four mechanistically distinct groups ofER-modulators were defined; full agonists (i.e. estradiol), two distinctclasses of partial agonists, represented by tamoxifen and raloxifene,and the pure antagonists, of which ICI182,780 is a representative member(McDonnell et al., Mol. Endocrinol. 9:659-669 (1995); Tzukerman et al.,Mol. Endocrinol. 8:21-30 (1994)). These results provide a mechanisticexplanation for the observed differences in the biological activities ofsome ER-modulators and indicate that the mechanism by which ER operatesin different tissues is not identical.

[0013] Interestingly, the agonist activity exhibited by ER-modulators,such as estrogen and tamoxifen, in these in vitro systems reflects theiractivity in the reproductive tracts of whole animals. This correlationdoes not extend to bone, however, where estradiol, tamoxifen andraloxifene, which display different degrees of AF-1/AF-2 agonistactivity, all effectively protect against bone loss in theovariectomized rat model. Thus, with the exception of the steroidal pureantiestrogens (ie, ICI182,780), all known classes of ER modulatorsappear to protect against bone loss in humans and relevant animalmodels, while they display different degrees of estrogenic activity inother tissues (Chow et al., J. Clin. Invest. 89:74-78 (1992); Love etal., New Engl. J. Med. 326:852-856 (1992); Draper et al., BiochemicalMarkers of Bone and Lipid Metabolism in Healthy Postmenopausal Women. InC. Christiansen and B. Biis (eds) Proceedings 1993. Fourth InternationalSymposium on Osteoporosis and Consensus Development Conference,Handelstrykkeriet, Aalborg; Wagner et al., Proc. Natl. Acad. Sci. USA93:8739-8744 (1996); Black et al., J. Clin. Invest 93:63-69 (1994)).

[0014] A series of non-steroidal compounds that retain beneficialcharacteristics such as osteoprotective activity while minimizing anyundesirable side effects would be most advantageous. While it ispresently accepted that the pharmacophore backbone mentioned above isresponsible for estrogen receptor binding specificity, it has now beendiscovered that certain novel estrogen binding ligands can beconstructed as described herein which incorporate particular moietiesonto such pharmacophore-based compounds, thereby maximizing beneficialcharacteristics such as osteoprotective function while minimizingundesirable characteristics such as an increased risk of cancer.

[0015] The present invention provides selective estrogen receptormodulators, which retain beneficial characteristics while minimizingundesirable side effects such as increased risk of cancer. SUMMARY OFTHE INVENTION

[0016] The present invention describes compounds represented by Formula(I):

[0017] wherein R¹-R⁵ are defined below.

[0018] The present invention is also directed to pharmaceuticalcompositions comprising one or more compounds of Formula (I).

[0019] In addition, the present invention is directed to methods for thetreatment and/or prevention of estrogen stimulated diseases includingbreast, uterine, ovarian, prostate and colon cancer, osteoporosis,cardiovascular disease, and benign proliferative disorders, comprising:administering to a host in need of such treatment a therapeuticallyeffective amount of a compound of Formula (I).

[0020] The present invention further provides methods of modulating theestrogen receptor in a patient comprising the step of administering tothe patient a therapeutically effective amount of a compound of Formula(I).

[0021] The present invention further provides pharmaceuticalcompositions including compounds of Formula (I) and a pharmaceuticallyacceptable carrier.

DETAILED DESCRIPTION OF THE INVENTION

[0022] This invention pertains to compounds of Formula (I) as selectiveestrogen receptor modulators:

[0023] wherein R¹ is selected from the group consisting of

[0024] R² is selected from the group consisting of H, C₁₋₈ alkyl andhalo;

[0025] R³ is selected from the group consisting of H, C₁₋₈ alkyl, C₁₋₈alkylenyl, halo, or CN;

[0026] alternatively R² and R³, together with the atoms to which theyare attached, form a six- or seven-membered ring structure where one ormore of the atoms forming the ring may be oxygen;

[0027] R⁴ is selected from the group consisting of H, OH, C₁₋₈ alkyl,OC₁₋₈ alkyl and halo;

[0028] R⁵ is selected from the group consisting of H, OH, CN, nitro,C₁₋₈ alkyl, OC₁₋₈ alkyl and halo;

[0029] R⁶ is selected from the group of H, OH, CN, OC₁₋₈ alkyl methyl,ethyl, propyl and butyl;

[0030] R⁷ is selected from the group consisting of H, aryl, C₁₋₈ alkyl,OH, and OC₁₋₈ alkyl;

[0031] R⁸ is selected from the group consisting of aryl, C₁₋₈ alkyl, OH,and OC₁₋₈ alkyl, wherein said R⁸ is optionally substituted with 1 to 2substituents selected from halo, nitro, OH, CN, C₁₋₄ alkyl, OC₁₋₄ alkyl,NH₂, and NHC(O)OC(CH₃)₃;

[0032] X is selected from the group consisting of O or NH, wherein whenX is O, R⁶ is other than OH; and, the broken line represents an optionaldouble bond.

[0033] According to some embodiments, R³ is CH₃ or R³ is CN or R³ isCH═CH₂. In further embodiments, R² is H.

[0034] In yet further embodiments of the present invention, compounds ofFormula (1) include:

[0035] a)3-{4-[6-(3-Methoxy-phenyl)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenyl}-acrylicacid;

[0036] b) 3-{4-[6-(4-Methoxy-phenyl)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenyl}-acrylic acid;

[0037] c)3-{4-[6-(3-Hydroxy-phenyl)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenyl}-acrylicacid;

[0038] d)3-{4-[6-(4-Hydroxy-phenyl)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenyl}-acrylicacid;

[0039] e) 5-{2-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-vinyl}-1H-tetrazole;

[0040] f)3-[4-(6-Phenyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl)-phenyl]-acrylicacid;

[0041] g)3-[4-(2-Hydroxy-6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenyl]-acrylicacid;

[0042] h)3-{4-[2-Hydroxy-6-(3-hydroxy-phenyl)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenyl}-acrylicacid;

[0043] i)3-{4-[2-Hydroxy-6-(4-hydroxy-phenyl)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenyl}-acrylicacid;

[0044] j)5-{2-[4-(6-Phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenyl]-vinyl}-1H-tetrazole;

[0045] k)5-{2-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-vinyl}-1-methyl-1H-tetrazole;

[0046] l)5-(2-{4-[6-(3-Methoxy-phenyl)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenyl}-vinyl)-1H-tetrazole;

[0047] m)3-[4-(6-Hydroxy-2-phenyl-3,4-dihydro-naphthalen-1-yl)-phenyl]-acrylicacid;

[0048] n)3-[4-(6-Hydroxy-2-phenyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-phenyl]-acrylicacid;

[0049] o)3-[4-(6-Phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenyl]-propionicacid;

[0050] p)3-[4-(6-Hydroxy-2-phenyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-phenyl]-acrylicacid;

[0051] q)3-[4-(6-Hydroxy-2-phenyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-phenyl]-acrylicacid;

[0052] r) 3-[4-(3-Phenyl-2H-chromen-4-yl)-phenyl]-acrylic acid;

[0053] s) 3-[4-(2-Phenyl-3,4-dihydro-naphthalen-1-yl)-phenyl]-acrylicacid;

[0054] t)3-[4-(2-Phenyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-phenyl]-acrylic acid;

[0055] u)3-[4-(6-Phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenyl]-acrylicacid;

[0056] v)N-{3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acryloyl}-methanesulfonamide;

[0057] w)N-{3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acryloyl}-benzenesulfonamide;

[0058] x)N-{3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acryloyl}-C-phenyl-methanesulfonamide;

[0059] y)N-{3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acryloyl}-3-nitro-benzenesulfonamide;

[0060] z)N-{3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acryloyl}-4-nitro-benzenesulfonamide;

[0061] aa)N-{3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acryloyl}-2-methyl-benzenesulfonamide;

[0062] ab)N-{3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acryloyl}-4-methyl-benzenesulfonamide;

[0063] ac)N-{3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acryloyl}-2-nitro-benzenesulfonamide;

[0064] ad)N-{3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acryloyl}-C,C,C-trifluoro-methanesulfonamide;

[0065] ae)N-{3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acryloyl}-4-methoxy-benzenesulfonamide;

[0066] af)4-Chloro-N-{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-benzenesulfonamide;

[0067] ag)4-Cyano-N-{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-benzenesulfonamide;

[0068] ah)N-{3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acryloyl}-3-trifluoromethyl-benzenesulfonamide;

[0069] ai)2-Chloro-N-{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-benzenesulfonamide;

[0070] aj)3-Chloro-N-{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-benzenesulfonamide;

[0071] ak)N-{3-[4-(2-Phenyl-3,4-dihydro-naphthalen-1-yl)-phenyl]-acryloyl}-methanesulfonamide;

[0072] al)N-{3-[4-(2-Phenyl-3,4-dihydro-naphthalen-1-yl)-phenyl]-acryloyl}-benzenesulfonamide;

[0073] am)N-{3-[4-(3-Phenyl-2H-chromen-4-yl)-phenyl]-acryloyl}-methanesulfonamide;

[0074] an)N-{3-[4-(3-Phenyl-2H-chromen-4-yl)-phenyl]-acryloyl}-benzenesulfonamide;

[0075] ao)4-{3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acryloylsulfamoyl}-benzoicacid methyl ester;

[0076] ap)N-{3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acryloyl}-2-trifluoromethyl-benzenesulfonamide;

[0077] aq)N-{3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acryloyl}-3-methyl-benzenesulfonamide;

[0078] ar)N-{3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acryloyl}-4-hydroxy-benzenesulfonamide;

[0079] as)N-{3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acryloyl}-3-methoxy-benzenesulfonamide;

[0080] at)N-{3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acryloyl}-4-trifluoromethyl-benzenesulfonamide;

[0081] au)N-{3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acryloyl}-3-hydroxy-benzenesulfonamide;

[0082] av)N-(2-Cyano-ethyl)-3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acrylamide;

[0083] aw)N-{3-[4-(6-Phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenyl]-acryloyl}-methanesulfonamide;

[0084] ax) N-{3-[4-(6-Phenyl-8,9-dihydro-7H-benzocyclohepten-5-1yl)-phenyl]-acryloyl}-benzenesulfonamide;

[0085] ay)C-Phenyl-N-{3-[4-(2-phenyl-3,4-dihydro-naphthalen-1-yl)-phenyl]-acryloyl}-methanesulfonamide;

[0086] az)C-Phenyl-N-{3-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenyl]-acryloyl}-methanesulfonamide;

[0087] ba) 3-Chloro-propane-1-sulfonic acid{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-amide; bb)(4-{3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acryloylsulfamoyl}-phenyl)-carbamicacid tert-butyl ester;

[0088] bc) 3-Piperidin-1-yl-propane-1-sulfonic acid{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-amide;

[0089] bd)4-Amino-N-{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-benzenesulfonamide;

[0090] be) Ethanesulfonic acid{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-amide;

[0091] bf)2-Dimethylamino-N-(4-{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloylsulfamoyl}-phenyl)-acetamide;

[0092] bg) Propane-2-sulfonic acid{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-amide;

[0093] bh)N-{3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acryloyl}-C-(4-fluoro-phenyl)-methanesulfonamide;

[0094] bi)4-{3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acryloylsulfamoyl}-benzoicacid;

[0095] bj)N-(4-{3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acryloylsulfamoyl}-phenyl)-acetamide;

[0096] bk) 2,2,2-Trifluoro-ethanesulfonic acid{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-amide;

[0097] bl) 3-Chloro-propane-1-sulfonic acid{3-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenyl]-acryloyl}-amide;

[0098] bm)C,C,C-Trifluoro-N-{3-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenyl]-acryloyl}-methanesulfonamide;

[0099] bn) 3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-N-hydroxy-acrylamide;

[0100] bo) 3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-N-methoxy-acrylamide;

[0101] bp) 3-Piperidin-1-yl-propane-1-sulfonic acid{3-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenyl]-acryloyl}-amide;

[0102] bq)C-(4-Fluoro-phenyl)-N-{3-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenyl]-acryloyl}-methanesulfonamide;

[0103] br) Thiophene-2-sulfonic acid{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-amide;

[0104] bs)N-{3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acryloyl}-C-(4-trifluoromethyl-phenyl)-methanesulfonamide;and,

[0105] bt)4-{3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acryloylsulfamoyl}-N-methyl-benzamide.

[0106] This invention also provides pharmaceutical compositions for thetreatment and/or prevention of breast, uterine, ovarian, prostrate andcolon cancer, osteoporosis, cardiovascular disease, and benignproliferative disorders. Pharmaceutical compositions of the presentinvention include any of the above compounds and a pharmaceuticallyacceptable carrier.

[0107] Another embodiment of the present invention provides a method oftreating breast, uterine, ovarian, prostate and colon cancer,osteoporosis, cardiovascular disease, endometriosis, uterine fibroid,Alzheimer's disease, macular degeneration, urinary incontinence, type IIdiabetes, and benign proliferative disorders, comprising: administeringto a host in need of such treatment a therapeutically effective amountof a compound of Formula (I).

[0108] The present invention further provides methods of modulating theestrogen receptor in a patient comprising the step of administering tothe patient a therapeutically effective amount of a compound of Formula(I).

[0109] Also included in the present invention are compounds of Formula(II):

[0110] wherein R¹ is selected from the group consisting of

[0111] R⁶ is selected from the group of H, methyl, ethyl, propyl andbutyl;

[0112] R⁷ is selected from the group consisting of aryl and C₁₋₈ alkyl,optionally substituted with one or more substituent groups;

[0113] R⁸, R⁹, R¹⁰ and R¹¹ are the same or different, and areindependently selected from the group consisting of: H, C₁₋₈ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, aryl, NO₂, NH₂ OH, OC₁₋₈ alkyl, CHO, COOH, haloand CN, wherein said R⁸ is optionally substituted with 1 to 2substituents selected from halo, nitro, OH, CN, C₁₋₄ alkyl, OC₁₋₄ alkyl,NH₂, and NHC(O)OC(CH₃)₃.

Definitions

[0114] The compounds of the present invention may contain anasymmetrically substituted carbon atom, and may be isolated in opticallyactive or racemic forms. It is well known in the art how to prepareoptically active forms, such as by resolution of racemic forms or bysynthesis from optically active starting materials. All chiral,diastereomeric, racemic forms and all geometric isomeric forms of astructure are intended, unless the specific stereochemistry or isomerform is specifically indicated.

[0115] The term “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms. Example s of alkyl include, but arenot limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl,t-butyl, n-pentyl, and s-pentyl. In addition, the term is intended toinclude both unsubstituted and substituted alkyl groups, the latterreferring to alkyl moieties having one or more hydrogen substituentsreplaced by, but not limited to halogen, hydroxyl, carbonyl, alkoxy,ester, ether, cyano, phosphoryl, amino, imino, amido, sulfhydryl,alkythio, thioester, sulfonyl, nitro, heterocyclo, aryl or heteroaryl.It will also be understood by those skilled in the art that thesubstituted moieties themselves can be substituted as well whenappropriate. The term “haloalkyl” as used herein refers to an alkylsubstituted with one or more halogens.

[0116] The terms “linear and cyclic heteroalkyl” are defined inaccordance with the term “alkyl” with the suitable replacement of carbonatoms with some other atom such as nitrogen or sulfur which would rendera chemically stable species.

[0117] The terms “halo” or “halogen” as used herein refer to fluoro,chloro, bromo and iodo. The term “aryl” is intended to mean an aromaticcyclic or bicyclic ring structure containing from 5 to 13 ring atoms,including compounds, such as, for example phenyl, indanyl and naphthyl.In addition, the term aryl is intended to include both unsubstituted andsubstituted aryl groups, the latter referring to aryl moieties havingone or more hydrogen substituents replaced by, for example, halogen,hydroxyl, carbonyl, alkoxy, keto, ester, ether, cyano, phosphoryl,amino, imino, amido, sulfhydryl, alkythio, thioester, sulfonyl, nitro,and/or heterocyclo. The term “haloaryl” as used herein refers to an arylmono, di or tri substituted with halogen atoms.

[0118] As used herein, the terms “cycloalkyl” “bicycloalkyl”“carbocycle” or “carbocyclic residue” are intended to mean any stable 3-to 7-membered monocyclic or bicyclic or 7- to 13-membered bicyclic ortricyclic, any of which may be saturated, partially unsaturated, oraromatic. Example s of such carbocycles include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,adamantyl, cyclooctyl,; [3.3.0]bicyclooctane, [4.3.0]bicyclononane,[4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl,naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).

[0119] As used herein, the term “heterocycle” or “heterocyclic system”or “heterocyclyl” is intended to mean a stable 5- to 7-memberedmonocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ringwhich is partially unsaturated or unsaturated (aromatic), and whichconsists of carbon atoms and from 1 to 4 heteroatoms independentlyselected from the group consisting of N, O and S and including anybicyclic group in which any of the above-defined heterocyclic rings isfused to a benzene ring. The nitrogen and sulfur heteroatoms mayoptionally be oxidized. The heterocyclic ring may be attached to itspendant group at any heteroatom or carbon atom which results in a stablestructure. The heterocyclic rings described herein may be substituted oncarbon or on a nitrogen atom if the resulting compound is stable. Ifspecifically noted, a nitrogen in the heterocycle may optionally bequaternized. It is preferred that when the total number of S and O atomsin the heterocycle exceeds 1, then these heteroatoms are not adjacent toone another. It is preferred that the total number of S and O atoms inthe heterocycle is not more than 1. As used herein, the term “aromaticheterocyclic system” or “heteroaryl” is intended to mean a stable 5- to7-membered monocyclic or bicyclic or 7- to 10-membered bicyclicheterocyclic aromatic ring which consists of carbon atoms and from 1 to4 heterotams independently selected from the group consisting of N, Oand S. It is preferred that the total number of S and O atoms in thearomatic heterocycle is not more than 1.

[0120] Example s of heterocycles include, but are not limited to,1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl,3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl,6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl,benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl,b-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl,2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl,furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl,indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl.,oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl,phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl,phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl,4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl,pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole,pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl,pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl,quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl,xanthenyl. Preferred heterocycles include, but are not limited to,pyridinyl, piperidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl,imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl,benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinoyl.Also included are fused ring and spiro compounds containing, forexample, the above heterocycles.

[0121] The term “heteroaryl” further includes a 5-membered or 6-memberedheterocyclic aromatic group that can optionally carry a fused benzenering and that can be unsubstituted or substituted.

[0122] As used herein, “pharmaceutically acceptable salts” refer toderivatives of the disclosed compounds wherein the parent compound ismodified by making acid or base salts thereof. Example s ofpharmaceutically acceptable salts include, but are not limited to,mineral or organic acid salts of basic residues such as amines; alkalior organic salts of acidic residues such as carboxylic acids; and thelike. The pharmaceutically acceptable salts include the conventionalnon-toxic salts or the quaternary ammonium salts of the parent compoundformed, for example, from non-toxic inorganic or organic acids. Forexample, such conventional non-toxic salts include those derived frominorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic,phosphoric, nitric and the like; and the salts prepared from organicacids such as acetic, propionic, succinic, glycolic, stearic, meglumine,lysine, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic,hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic,2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, and the like.

[0123] The pharmaceutically acceptable salts of the present inventioncan be synthesized from the parent compound which contains a basic oracidic moiety by conventional chemical methods. Generally, such saltscan be prepared by reacting the free acid or base forms of thesecompounds with a stoichiometric amount of the appropriate base or acidin water or in an organic solvent, or in a mixture of the two;generally, nonaqueous media like ether, ethyl acetate, ethanol,isopropanol, or acetonitrile are preferred. Lists of suitable salts arefound in Remington's Pharmaceutical Sciences, 18th ed., Mack PublishingCompany, Easton, Pa., 1990, p. 1445, the disclosure of which is herebyincorporated by reference in it's entirety as though set forth in full.

[0124] The phrase “pharmaceutically acceptable” is employed herein torefer to those compounds, materials, compositions, and/or dosage formswhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of human beings and animals withoutexcessive toxicity, irritation, allergic response, or other problem orcomplication commensurate with a reasonable benefit/risk ratio.

[0125] “Prodrugs”, as the term is used herein, are intended to includeany covalently bonded carriers which release an active parent drug ofthe present invention in vivo when such prodrug is administered to amammalian subject. Since prodrugs are known to enhance numerousdesirable qualities of pharmaceuticals (i.e., solubility,bioavailability, manufacturing, etc.) the compounds of the presentinvention may be delivered in prodrug form. Thus, the present inventionis intended to cover prodrugs of the presently claimed compounds,methods of delivering the same, and compositions containing the same.Prodrugs of the present invention are prepared by modifying functionalgroups present in the compound in such a way that the modifications arecleaved, either in routine manipulation or in vivo, to the parentcompound. Prodrugs include compounds of the present invention wherein ahydroxy, amino, or sulfhydryl group is bonded to any group that, whenthe prodrug of the present invention is administered to a mammaliansubject, it cleaves to form a free hydroxyl, free amino, or freesulfydryl group, respectively. Example s of prodrugs include, but arenot limited to, acetate, formate, and benzoate derivatives of alcoholand amine functional groups in the compounds of the present invention.

[0126] “Substituted” is intended to indicate that one or more hydrogenson the atom indicated in the expression using “substituted” is replacedwith a selection from the indicated group(s), provided that theindicated atom's normal valency is not exceeded, and that thesubstitution results in a stable compound. When a substituent is keto(i.e., ═O) group, then 2 hydrogens on the atom are replaced.

[0127] For purposes of the present invention the term “substitutentgroup” refers to R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ or any group selectedfrom the group consisting of —NO₂, —NH₂, —COOH, —CHO, OH, alhoxy keto,—SO₂, halogen, hydrogen, —CN and aryl.

[0128] As used herein, the term “anti cancer” or “anti-proliferative”agent includes, but is not limited to, altretamine, busulfan,chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine, melphalan,thiotepa, cladribine, fluorouracil, floxuridine, gemcitabine,thioguanine, pentostatin, methotrexate, 6-mercaptopurine, cytarabine,carmustine, lomustine, streptozotocin, carboplatin, cisplatin,oxaliplatin, iproplatin, tetraplatin, lobaplatin, JM216, JM335,fludarabine, aminoglutethimide, flutamide, goserelin, leuprolide,megestrol acetate, cyproterone acetate, tamoxifen, anastrozole,bicalutamide, dexamethasone, diethylstilbestrol, prednisone, bleomycin,dactinomycin, daunorubicin, doxirubicin, idarubicin, mitoxantrone,losoxantrone, mitomycin-c, plicamycin, paclitaxel, docetaxel, topotecan,irinotecan, 9-amino camptothecan, 9-nitro camptothecan, GS-211,etoposide, teniposide, vinblastine, vincristine, vinorelbine,procarbazine, asparaginase, pegaspargase, octreotide, estramustine,hydroxyurea and the compounds disclosed in U.S. Pat. No. 5,681,835,issued to Timothy Wilson on Mar. 2, 1999. THF is an abbreviation fortetrahydrofuran; DME is an abbreviation for ethylene glycol dimethylether.

[0129] For purposes of the present invention the term “host” refers tomammals including humans.

Dosage and Formulation

[0130] The selective estrogen receptor modulator compounds of thisinvention can be administered as treatment for or prevention of canceror other disease states by any means that produces contact of the activeagent with the agent's site of action in the body of a mammal. They canbe administered by any conventional means available for use inconjunction with pharmaceuticals, either as individual therapeuticagents or in combination with other compounds according to the presentinvention and/or other therapeutic agents, such as anti-cancer oranti-proliferative agents. When used in combination, the therapeuticagents may be administered together or separately so long as thetherapeutic agents, or their active metabolites, are present in the hostduring an overlapping time period. The therapeutic agents can beadministered alone, but preferably are administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

[0131] The dosage administered will, of course, vary depending uponknown factors, such as the pharmacodynamic characteristics of theparticular agent and its mode and route of administration; the age,health and weight of the recipient; the nature and extent of thesymptoms; the kind of concurrent treatment; the frequency of treatment;and the effect desired. A daily dosage of active ingredient can beexpected to be about 0.001 to about 1000 milligrams per kilogram of bodyweight, with the preferred dose being about 0.1 to about 30 mg/kg.

[0132] Dosage forms of compositions suitable for administration containfrom about 1 mg to about 100 mg of active ingredient per unit. In thesepharmaceutical compositions the active ingredient will ordinarily bepresent in an amount of about 0.5-95% by weight based on the totalweight of the composition. The active ingredient can be administeredorally in solid dosage forms, such as capsules, tablets and powders, orin liquid dosage forms, such as elixirs, syrups and suspensions. It canalso be administered parenterally, in sterile liquid dosage forms.

[0133] Gelatin capsules contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract. Liquid dosage forms fororal administration can contain coloring and flavoring to increasepatient acceptance.

[0134] In general, water, a suitable oil, saline, aqueous dextrose(glucose), and related sugar solutions and glycols such as propyleneglycol or polyethylene glycols are suitable carriers for parenteralsolutions. Solutions for parenteral administration preferably contain awater soluble salt of the active ingredient, suitable stabilizingagents, and if necessary, buffer substances. Anti-oxidizing agents suchas sodium bisulfite, sodium sulfite, or ascorbic acid, either alone orcombined, are suitable stabilizing agents. Also used are citric acid andits salts, and sodium EDTA. In addition, parenteral solutions cancontain preservatives, such as benzalkonium chloride, methyl- orpropyl-paraben and chlorobutanol. Suitable pharmaceutical carriers aredescribed in Remington's Pharmaceutical Sciences, 18th ed., MackPublishing Company, Easton, Pa., 1990, a standard reference text in thisfield, the disclosure of which is hereby incorporated by reference.

Synthesis

[0135] The compounds of the present invention can be prepared in anumber of ways well known to one skilled in the art of organicsynthesis. The compounds of the present invention can be synthesizedusing the methods described below, together with synthetic methods knownin the art of synthetic organic chemistry, or variations thereon asappreciated by those skilled in the art. Preferred methods include, butare not limited to, those described below. All references cited hereinare hereby incorporated in their entirety herein by reference.

[0136] The novel compounds of this invention may be prepared using thereactions and techniques described in this section. The reactions areperformed in solvents appropriate to the reagents and materials employedand are suitable for the transformations being effected. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including choice ofsolvent, reaction atmosphere, reaction temperature, duration of theexperiment and workup procedures, are chosen to be the conditionsstandard for that reaction, which should be readily recognized by oneskilled in the art. It is understood by one skilled in the art oforganic synthesis that the functionality present on various portions ofthe molecule must be compatible with the reagents and reactionsproposed. Such restrictions to the substituents which are compatiblewith the reaction conditions will be readily apparent to one skilled inthe art and alternate methods must then be used. Isolation of thedesired compounds of this invention can be achieved using standardchromatographic techniques known to those skilled in the art.

[0137] Depending on the structure of the final product, it will beappreciated by those skilled in the art that protecting groups orprecursor functionality convertable to the desired groups may bedesireable. Protecting groups and their use in synthesis are describedin Green and Wuts, Protective Groups in Organic Synthesis, (Wiley 1991).

[0138] Conversion of substituted acrylic acid I to an acylsulfonamide IIemploys a coupling reaction with a sulfonamide R²SO₂NH2 (Scheme 1). Thecoupling reaction is performed in the presence of DMAP and1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (EDC).Other reagents, besides EDC, which can be employed in this couplingreaction include HATU, TBTU, BOP, pyBOP, EDC, CDI, and DCC. Suitablesolvents for the coupling reaction include CH₂Cl₂.

[0139] Acylsulfonamides VIII are prepared from substituted1,2-dihydronaphthalene III or substituted dihydro benzocycloheptene IIIin five steps: 1) Heck coupling, 2) halogenation, 3) Suzuki coupling, 4)hydrolysis, and 5) sulfonylation reaction.

[0140] 1. Heck Coupling Reaction. Substituted 1,2-dihydro-naphthaleneIII or substituted dihydro benzocycloheptene III (X=halo, tosylate,mesylate or triflate) is coupled with a methyl acrylate ester in thepresence of a palladium catalyst and a base to form benzocyclohexene ordihydro benzocycloheptene IV.

[0141] Solvents for the Heck reaction are well known to the skilledartisan and include amides (e.g., dimethylformamide, dimethylacetamide,N-methylpyrrolidone), nitriles (e.g., acetonitrile, propionitrile,butyronitrile), ethers (e.g., dimethoxyethane, tetrahydrofuran), andhydrocarbons (e.g., cyclohexane, benzene, toluene, xylene)

[0142] Palladium catalysts suitable for the Heck coupling reactioninclude, but are not limited to, Pd(OAc)₂, PdCl₂(CH₃CN)₂, or Pd₂(dba)₃.

[0143] Bases which are useful in the Heck reaction include alkalinemetal carbonates and hydrogen carbonates, alkaline metal acetates,alkaline metal phosphates, and tertiary amines. Example s of bases forthe Heck coupling reaction include TEA, PMP(1,2,2,6,6-pentamethylpiperidine), Na₂CO₃, Ag₂CO₃, or NaHCO₃. Preferredbases are tertiary amines.

[0144] After the reaction is complete, the catalyst may be obtained as asolid and separated off by filtration. The crude product is freed of thesolvent or the solvents and is subsequently purified by methods known tothose skilled in the art e.g. by chromatography.

[0145] For an example of the preparation of dihydro benzocyclohepteneIV, see J. Chem. Soc. B, 1969, 638-643.

[0146] 2. Halogenation

[0147] Halogenation of benzocyclohexene or dihydro benzocycloheptene IVcan be performed by employing a variety of electrophilic halogenatingreagents such as pyridinium bromide perbromide or NBS to afford halobenzocyclohexene and halo dihydro benzocycloheptene V. Halogenationreactions are well known to those skilled in the art and are describedin the chemical literature. See for example: Larock, R. C. ComprehensiveOrganic Transformations, VCH Publishers, New York, 1989.

[0148] 3. Suzuki Coupling Reaction

[0149] A Suzuki coupling of a halo benzocyclohexene or a halo dihydrobenzocycloheptene V with a boronic acid (R⁶—Ph)B(OH)₂ in the presence ofa palladium catalyst and a base provides bis-aryl substitutedbenzocyclohexene or bis-aryl substituted dihydro benzocycloheptene VI.Suitable solvents for this coupling include, but not limited to, THF,H₂O, DMSO, Et2O, toluene, DMF, dioxane and ethanol, i-PrOH, or acombination of two or more of these solvents. The reaction is carriedout in the presence of a palladium catalyst, for example, [(C₆H₅)₃P]₄Pd,[(C₆H₅)₃P]₂PdCl₂, PdCl₂(dppf), or Pd(OAc)₂. Suitable bases for theSuzuki coupling reaction include TEA, KOH, TlOH, Na₂CO₃, Cs₂CO₃, andK₂CO₃. See, for example, Miyaura, N., Suzuki, A. Chem. Rev. 1995, 95,2457-2483; Suzuki, A., J. Organometallic Chem. 1999, 576, 147-168; andSuzuki, A. in Metal-catalyzed Cross-coupling Reactions, Diederich, F.,and Stang, P. J., Eds.; Wiley-VCH: New York, 1998, pp. 49-97.

[0150] 4. Hydrolysis.

[0151] Conversion of bis-aryl substituted benzocyclohexene or bis-arylsubstituted dihydro benzocycloheptene VI to the correspondingsubstituted acrylic acid VII is carried out using standard hydrolysisreaction. Suitable bases include hydroxides or carbonates in an ether,alcohol, or aqueous alcohol or aqueous ether solvent systems. SeeLarock, R. C., Comprehensive Organic Transformations, VCH Publishers,New York, 1989.

[0152] 5. Sulfonylation.

[0153] Conversion of substituted acrylic acid VII to an acylsulfonamideVII employs a coupling reaction with a sulfonamide R²SO₂NH₂. See theexperimental section of Scheme 1.

[0154] Benzopyran XIII can be prepared from substituted 2H-chromene IXusing a reaction sequence similar to that of Scheme 2 with severalmodifications. One is that the halogenation and suzuki coupling stepsare not needed in the synthesis of benzopyran XIII since the phenylbearing substituent R⁶ is already present in the starting material2H-chromene IX. The second modification is that a reaction to convertthe OH group 2H-chromene IX to an tosylate, mesylate or triflate isneeded for a subsequent coupling reaction. The preparation of benzopyranXIII from substituted 2H-chromene IX takes four steps: 1) preparation ofaryl-X coupling partner for a subsequent Heck reaction, e.g.trifluoro-methanesulfonyl ester, 2) Heck coupling reaction, 3)hydrolysis, and 4) sulfonylation. Preparation oftrifluoromethanesulfonyl ester X from phenol IX (step 1) is well knownin the literature. See: Larock, R. C. Comprehensive OrganicTransformations, VCH Publishers, New York, 1989. Subsequenttransformations of aryl-OTf X to Benzopyran XIII (steps 2-4) can beaccomplished using the method described in Scheme 2.

[0155] Tetrazole XV is prepared from benzaldehyde XIII in two steps. Thefirst step is a 1,2-addition of acetonitrile to benzaldehyde XIIIfollowed by elimination of water to provide cinnamonitrile XIV. A basesuch as KOH is used to deprotonate the hydrogen of the methyl group ofacetonitrile in this reaction. The second step involves an addition ofan azide to cinnamonitrile XIV to form tetrazole XV in the presence of aLewis acid catalyst. Optionally, compound XV may be furtherfunctionalized by methylation of the tetrazole group. Such N-methylationis well known in the art.

[0156] Dihydro benzocycloheptenyl tetrazole XIX can be prepared fromdihydro benzocycloheptenyl phenol XVI in three steps. Step 1)preparation of triflate XVII; step 2) Heck coupling, and step 3)tetrazole formation. The preparation of tetrazole XIX involves theaddition of an azide to cinnamonitrile XVIII in the presence of a Lewisacid catalyst. Optionally, compound XIX may be further functionalized bymethylation of the tetrazole group. See Scheme 4.

EXAMPLES

[0157] The invention can be further understood by the followingexamples. Other features of the invention will become apparent to thoseskilled in the art during the following description and exemplaryembodiments that are given for illustration and are not intended to belimiting thereof.

Example I Preparation ofN-{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-methanesulfonamide1b

[0158]

[0159] Procedure 1, Method A. To a solution of3-[4-(Z)-(1,2-diphenylbut-1-enyl)phenyl]-acrylic acid (1a, compound I,R³H, R⁶═H)(666 mg, 1.87 mmol) in CH₂Cl₂ (10 mL) was addedmethanesulfonamide (711 mg, 7.47 mmol),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC)(540mg, 2.82 mmol), and 4-dimethylaminopyridine(344 mg, 2.82 mmol). Afterstirring overnight the mixture was acidified with 1N HCl, and wasextracted with EtOAc. The combined organic layers were washed with brineand dried (MgSO₄). The solvent was removed under reduced pressure andthe residue was chromatographed (silica gel, 5% methanol/CH₂Cl₂) to givethe acylsulfonamide (1b) as a white solid (695 mg, 86%): ¹H NMR (CDCl₃)δ 7.61 (d, J=15.7 Hz, 1H), 7.39-7.09 (m, 12H), 6.91 (d, J=8.4 Hz, 2H),6.23 (d, J=15.7 Hz, 1H), 3.34 (s, 3H), 2.48 (q, J=7.3 Hz, 2H), 0.94 (t,J=7.3 Hz, 3H); ESI m/z: 430 (M−H⁻, 100%).

Example II Preparation ofN-{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-benzenesulfonamide1c

[0160]

[0161] Prepared from the coupling of 1a (compound I, R³═H, R⁶═H) andbenzene sulfonamide by the method described in Procedure 1, Method A.Yield (76%); ¹H NMR (CDCl₃) δ 8.41 (br. s, 1H), 8.08 (d, J=8.4 Hz, 2H),7.65-7.07 (m, 16H), 6.86 (d, J=8.4 Hz, 2H), 6.23 (d, J=15.7 Hz, 1H),2.46 (q, J=7.3 Hz, 2H), 0.92 (t, J=7.3 Hz, 3H); ESI m/z: 492 (M−H⁻,100%).

Example III Preparation ofN-{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-C-phenyl-methanesulfonamide1d

[0162]

[0163] Prepared from the coupling of 1a (compound I, R³=H, R⁶=H) and.-toluene sulfonamide by the method described in Procedure 1, Method A.Yield (61%); ¹H NMR (CDCl₃) δ 7.59 (d, J=15.7 Hz, 1H), 7.39-7.10 (m,17H), 6.90 (d, J=8.4 Hz, 2H), 6.13 (d, J=15.7 Hz, 1H), 4.68 (s, 2H),2.48 (q, J=7.3 Hz, 2H), 0.94 (t, J=7.3 Hz, 3H); ESI m/z: 506 (M−H⁻,100%)

Example IV Preparation of intermediate3-[4-(8,9-Dihydro-7H-benzocyclohepten-5-yl)-phenyl]-acrylic Acid MethylEster 2b

[0164]

[0165] To a solution of9-(4-bromophenyl)-6,7-dihydro-5H-benzocycloheptene (2a, compound III,R³=H, X=Br, n=2) (12.38 g, 41 mmol) in DMF (30 mL) was added methylacrylate (38.2 g, 444 mmol), triethylamine (29.0 g, 286 mmol), andbis(triphenylphosphine)palladium(II) chloride (7.0 g, 10.0 mmol). Themixture was placed in a pressure bottle and heated at 100° C. for 4days. The solvent was removed under reduced pressure and the residue waschromatographed (silica gel, 7.5 to 15% EtOAc/hexanes) to give the ester(2b) as a white solid (11.4 g, 90%): ¹H NMR (CDCl₃) δ 7.69 (d, J=15.7Hz, 1H), 7.45 (d, J=8.1 Hz, 2H), 7.24 (m, 5H), 6.98 (m, 1H), 6.52 (t,J=7.3 Hz, 1H), 6.43 (d, J=15.7 Hz, 1H), 3.81 (s, 3H), 2.65 (t, J=7.0 Hz,2H), 2.17 (m, 2H), 1.98 (m, 2H); APcI m/z: 346 (M+H+CH₃CN⁺, 100%).

Example V Preparation of intermediate3-[4-(6-Bromo-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenyl]-acrylic AcidMethyl Ester 2c

[0166]

[0167] To a solution of the olefin (2b) (5.44 g, 17.9 mmol) in CH₂Cl₂(300 mL) at 0° C. was added pyridinium bromide perbromide (90%, 7.0 g,19.6 mmol) in portions over 0.5 h. After stirring 1 h the solution waswashed with water, sat. NaHSO₃, water and was dried (MgSO₄). The solventwas removed under reduced pressure to give the bromide (2c) as an oil(6.85 g, 100%): ¹H NMR (CDCl₃) δ 7.69 (d, J=16.1 Hz, 1H), 7.50 (d, J=8.1Hz, 2H), 7.20 (m, 5H), 6.80 (d, J=7.3 Hz, 1H), 6.43 (d, J=16.1 Hz, 1H),3.81 (s, 3H), 2.79 (t, J=7.0 Hz, 2H), 2.60 (t, J=7.0 Hz, 2H), 2.30 (m,2H); APcI m/z: 424 (M+H+CH₃CN⁺, 100%).

Example VI Preparation of intermediate3-[4-(6-Phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenyl]-acrylicAcid Methyl Ester 2d

[0168]

[0169] To a solution of the bromide (2c) (6.85 g, 17.9 mmol) in DME (125mL) was added benzene boronic acid (3.25 g, 26.8 mmol),tetrakis(triphenylphosphine)palladium(0) (2.1 g, 1.8 mmol), and 2Naqueous sodium carbonate(13.5 mL). After refluxing overnight the solventwas removed under reduced pressure and the residue was chromatographed(silica gel, 7.5 EtOAc/hexanes to 100% EtOAc) followed byrecrystalization from EtOAc to give (2d) as a white solid (4.24 g, 62%):¹H NMR (CDCl₃) δ 7.58 (d, J=16.1 Hz, 1H), 7.20 (m, 10H), 6.92 (d, J=8.1Hz, 2H), 6.85 (dd, J=7.3, 1.1 Hz, 1H), 6.32 (d, J=16.1 Hz, 1H), 3.78 (s,3H), 2.82 (t, J=7.0 Hz, 2H), 2.40 (t, J=7.0 Hz, 2H), 2.20 (m, 2H); APcIm/z: 422 (M+H+CH₃CN⁺, 100%).

Example VII Preparation of3-[4-(6-Phenyl-8,9-dihydro-7H-benzo-cyclohepten-5-yl)-phenyl]-acrylicacid 2e

[0170]

[0171] To a solution of ester (2d) (4.2 g, 11.0 mmol) in methanol (370mL) and THF (225 mL) was added 1N KOH (188 mL). After stirring overnightthe mixture was heated to 50° C. for 0.5 h and was allowed to cool tort. After stirring 2 h the solvent was partially removed under reducedpressure, the mixture was acidified with 1N HCl, and was extracted withEtOAc. The combined organic layers were washed with water, brine andwere dried (MgSO₄). The solvent was removed under reduced pressure andthe residue was triturated (EtOAc) to give the acid (2e) as a whitesolid (3.86 g, 96%): ¹H NMR (CD₃OD) δ 7.54 (d, J=15.7 Hz, 1H), 6.28 (d,J=8.1 Hz, 2H), 7.27-7.08 (m, 8H), 6.89 (d, J=8.1 Hz, 2H), 6.76 (dd,J=7.3, 1.1 Hz, 1H), 6.34 (d, J=15.7 Hz, 1H), 2.83 (t, J=7.0 Hz, 2H),2.37 (t, J=7.0 Hz, 2H), 2.14 (m, 2H); ESI m/z: 365 (M−H⁻, 100%).

Example VIII Preparation ofN-{3-[4-(6-phenyl-8,9-dihydro-7H-benzo-cyclohepten-5-yl)-phenyl]-acryloyl}-methanesulfonamide2f

[0172]

[0173] Prepared from the coupling of 2e and methylsulfonamide by themethod described in Procedure 1, Method A. Yield (68%); ¹H NMR (CDCl₃) δ7.66 (d, J=15.7 Hz, 1H), 7.18 (m, 10H), 6.95 (d, J=8.1 Hz, 2H), 6.84 (d,J=7.3 Hz, 1H), 6.28 (d, J=15.7 Hz, 1H), 3.36 (s, 3H), 2.82 (t, J=7.0 Hz,2H), 2.41 (t, J=7.0 Hz, 2H), 2.19 (m, 2H); ESI m/z: 442 (M−H⁻, 100%).

Example IX Preparation ofN-{3-[4-(6-phenyl-8,9-dihydro-7H-benzo-cyclohepten-5-yl)-phenyl]-acryloyl}-benzenesulfonamide2 g

[0174]

[0175] Prepared from the coupling of 2e and benzene sulfonamide by themethod described in Procedure 1, Method A. Yield (70%); ¹H NMR (d6-DMSO)δ 12.25 (s, 1H), 7.94 (d, J=7.3 Hz, 2H), 7.66 (m, 3H), 7.42 (d, J=15.7Hz, 1H), 7.34-7.14 (m, 10H), 6.88 (d, J=8.1 Hz, 2H), 6.72 (d, J=7.3 Hz,1H), 6.48 (d, J=15.7 Hz, 1H), 2.79 (m, 2H), 2.28 (m, 2H), 2.09 (m, 2H);ESI m/z: 504 (M−H⁻, 100%).

Example XC-Phenyl-N-{3-[4-(6-phenyl-8,9-dihydro-7H-benzo-cyclohepten-5-yl)-phenyl]-acryloyl}-methanesulfonamide2h

[0176]

[0177] Prepared from the coupling of 2e and .-toluene sulfonamide by themethod described in Procedure 1, Method A. Yield (58%); ESI m/z: 518(M−H⁻, 100%).

Example XI Preparation of intermediate3-[4-(3,4-dihydro-naphthalen-1-yl)-phenyl]-acrylic acid methyl ester 2j

[0178]

[0179] Prepared from the Heck coupling of4-(4-bromophenyl)-1,2-dihydro-naphthalene (2i, compound III, R³=H, X=Br,n=1) and methyl acrylate by the general method described for example 2b(J. Chem. Soc. B, 1969, 638-643). Yield 74%; APcI m/z: 332 (M+H+CH₃CN⁺,100%).

Example XII Preparation of intermediate3-[4-(2-bromo-3,4-dihydro-naphthalen-1-yl)-phenyl]-acrylic Acid MethylEster 2k

[0180]

[0181] Prepared by the bromination of 2j by the general method describedfor example 2c. Yield 100%; ApcI m/z: 410 (M+H+CH₃CN⁺, 100%).

Example XIV Preparation of Intermediate3-[4-(2-phenyl-3,4-dihydro-naphthalen-1-yl)-phenyl]-acrylic Acid MethylEster 2l

[0182]

[0183] Prepared from the coupling of 2k and benzene boronic acid,(R⁶—Ph)B(OH)₂ where R⁶═H, by the general method described for example2d. Yield 50%; APcI m/z: 408 (M+H+CH₃CN⁺, 100%).

Example XV Preparation of Intermediate3-[4-(2-phenyl-3,4-dihydro-naphthalen-1-yl)-phenyl]-acrylic Acid 2m

[0184]

[0185] Prepared from the saponification of ester 2l by the generalmethod described for example 2e. Yield (77%). ¹H NMR (DMSO-d₆) δ 12.34(s, 1H), 7.52 (m, 3H), 7.23-7.00 (m, 10H), 6.53 (d, J=6.5 Hz, 1H), 6.45(d, J=15.7 Hz, 1H), 2.91 (br t, J=7.9 Hz, 2H), 2.71 (br t, J=7.9 Hz,2H); ESI m/z: 351 (M−H⁻, 100%).

Example XVI Preparation ofN-{3-[4-(2-phenyl-3,4-dihydro-naphthalen-1-yl)-phenyl]-acryloyl}-methanesulfonamide2n

[0186]

[0187] Prepared from the coupling of 2m and methylsulfonamide by themethod described in Procedure 1, Method A. Yield (57%); ESI m/z: 428(M−H⁻, 100%).

Example XVII Preparation ofN-{3-[4-(2-phenyl-3,4-dihydro-naphthalen-1-yl)-phenyl]-acryloyl}-benzenesulfonamide2o

[0188]

[0189] Prepared from the coupling of 2m and benzene sulfonamide by themethod described in Procedure 1, Method A. Yield (65%); ESI m/z: 490(M−H⁻, 100%).

Example XVIII Preparation of intermediate trifluoro-methanesulfonic acid4-(3-phenyl-2H-chromen-4-yl)-phenyl ester 3b

[0190]

[0191] To a solution of 4-(3-phenyl-2H-chromen-4-yl)-phenol (JustusLiebigs Ann. Chem. 1971, 744, 164-177.)(3a, compound IX, R³=H, R⁶=H)(3.18 g, 10.58 mmol) in CH₂Cl₂ (100 mL) at 0° C. was added pyridine(2.09 g, 26.5 mmol) followed by trifluoromethanesulfonic anhydride(3.68g, 13.2 mmol). The solution was stirred 15 min and was allowed to warmto rt. After stirring 2 h the mixture was diluted with water, and wasextracted with CH₂Cl₂. The combined organic layers were washed withwater, brine and dried (MgSO₄). The solvent was removed under reducedpressure and the residue was chromatographed (silica gel, 7.5%EtOAc/hexanes) to give the triflate 3b (compound X, R³═H, R⁶═H) as awhite solid (4.0 g, 88%); ¹H NMR (CDCl₃) δ 7.18 (m, 8H), 6.93 (m, 3H),6.86 (dt, J=7.5, 1.1 Hz, 1H), 6.75 (dd, J=7.9, 1.6 Hz, 1H), 5.10 (s,2H); ¹⁹F NMR (CDCl₃) δ −73.15.

Example XIX Preparation of intermediate3-[4-(3-phenyl-2H-chromen-4-yl)-phenyl]-acrylic Acid Methyl Ester 3c

[0192]

[0193] Prepared from the Heck coupling of 3b and methyl acrylate by thegeneral method described for example 2b. Yield (94%); APcI m/z: 410(M+H+CH₃CN⁺, 100%).

Example XX Preparation of Intermediate3-[4-(3-phenyl-2H-chromen-4-yl)-phenyl]-acrylic Acid 3d

[0194]

[0195] Prepared from the saponification (hydrolysis) of ester 3c by thegeneral method described for example 2e. Yield (86%); ESI m/z: 353(M−H⁻, 100%).

Example XXI Preparation ofN-{3-[4-(3-phenyl-2H-chromen-4-yl)-phenyl]-acryloyl}-methanesulfonamide3e

[0196]

[0197] Prepared from the coupling of 3d and methylsulfonamide by themethod described in Procedure 1, Method A. Yield (35%); ESI m/z: 430(M−H⁻, 100%).

Example XXII Preparation ofN-{3-[4-(3-phenyl-2H-chromen-4-yl)-phenyl]-acryloyl}-benzenesulfonamide3f

[0198]

[0199] Prepared from the coupling of 3d and benzene sulfonamide by themethod described in Procedure 1, Method A. Yield (46%); ESI m/z: 492(M−H⁻, 100%)

Example XXIII Preparation of intermediate3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acrylonitrile 4b

[0200]

[0201] A suspension of potassium hydroxide (85%, 260 mg, 3.9 mmol) inCH₃CN (25 mL) was heated to reflux and(Z)-1,2-Diphenyl-1-(4-formylphenyl)-1-butene (4a, compound XII¹, R³=H,R⁶=H) (Willson J. Med. Chem. 1994, 37, 1550-1552) (1.0 g, 3.18 mmol) wasadded in portions. After refluxing 5 min the mixture was diluted withwater and was extracted with EtOAc. The combined organic layers werewashed with brine and dried (MgSO₄). The solvent was removed underreduced pressure and the residue was chromatographed (silica gel, 15%EtOAc/hexanes) to give the nitrile (4b, compound XIV, R³═H, R⁶═H) as awhite solid (616 mg, 57%): ¹H NMR (CDCl₃) δ 7.39-7.07 (m, 13H), 6.91 (d,J=8.4 Hz, 2H), 5.69 (d, J=16.9 Hz, 1H), 2.48 (q, J=7.3 Hz, 2H), 0.94 (t,J=7.3 Hz, 3H); HRMS calcd. for C₂₅H₂₁N (M+H⁺) 335.1674; found 335.1679.

Example XXIV Preparation of5-{2-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-vinyl}-1H-tetrazole 4c

[0202]

[0203] To a solution of aluminum chloride (1.82 g, 13.5 mmol) in THF (20mL) at 0° C. was added sodium azide (1.77 g, 27 mmol) then nitrile (4b)(888 mg, 2.65 mmol). The mixture was stirred 10 min and was heated toreflux. After refluxing overnight the mixture was diluted with 1N HCl,and was extracted with EtOAc. The combined organic layers were washedwith water, brine and were dried (MgSO₄). The solvent was removed underreduced pressure and the residue was chromatographed (silica gel, 10-20%methanol/CH₂Cl₂) to give the tetrazole (4c, compound XV, R³=H, R⁶H) as awhite solid (700 mg, 70%): ¹H NMR (CDCl₃) δ 7.63 (d, J=16.5 Hz, 1H),7.39-7.11 (m, 12H), 6.98 (d, J=16.5 Hz, 1H), 6.91 (d, J=8.4 Hz, 2H),2.48 (q, J=7.3 Hz, 2H), 0.94 (t, J=7.3 Hz, 3H); ESI m/z: 377 (M−H⁻,100%).

Example XXV Preparation of Intermediate trifluoro-methanesulfonic acid4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenyl Ester 5b

[0204]

[0205] To a solution of6,7-dihydro-8-phenyl-9-(4-hydroxyphenyl)-5H-benzocycloheptene (J. Med.Chem. 1986, 29, 2053-2059) (5a, compound XVI, R³=H, R⁶=H) (500 mg, 1.60mmol) in CH₂Cl₂ (15 mL) at 0° C. was added pyridine (316 mg, 4.0 mmol)followed by trifluoromethanesulfonic anhydride(560 mg, 2.0 mmol). Thesolution was stirred 30 min and was diluted with water, and wasextracted with CH₂Cl. The combined organic layers were washed withwater, brine and dried (MgSO₄). The solvent was removed under reducedpressure and the residue was chromatographed (silica gel, 7.5%EtOAc/hexanes) to give the triflate (5b, compound XVII, R³=H, R⁶=H) as awhite solid (665 mg, 94%): ¹H NMR (CDCl₃) δ 7.30-7.09 (m, 12H), 6.82(dd, J=7.3, 1.5 Hz, 1H), 2.81 (t, J=7.0 Hz, 2H), 2.40 (t, J=7.0 Hz, 2H),2.20 (m, 2H).

Example XXVI Preparation of Intermediate3-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenyl]-acrylonitrile5c

[0206]

[0207] To a solution of the triflate (5b) (560 mg, 1.25 mmol) in DMF (6mL) was added acrylonitrile (2.10 g, 39.6 mmol), triethylamine (2.90 g,28.6 mmol), and bis(triphenyl-phosphine)palladium(II) chloride (700 mg,1.0 mmol). The mixture was placed in a pressure bottle and heated at100° C. for 4 days. The solvent was removed under reduced pressure andthe residue was chromatographed (silica gel, 15% EtOAc/hexanes) to givethe nitrile (5c, compound XVIII, R³=H, R⁶=H) as a white solid (199 mg,46%): ¹H NMR (CDC1,) δ 7.30-7.13 (m, 11H), 6.94 (d, J=8.1 Hz, 2H), 6.82(dd, J=7.3, 1.1 Hz, 1H), 5.75 (d, J=16.5 Hz, 1H), 2.81 (t, J=7.0 Hz,2H), 2.40 (t, J=7.0 Hz, 2H), 2.19 (m, 2H)

Example XXVII Preparation of5-{2-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenyl]-vinyl}-1H-tetrazole5d

[0208]

[0209] To a solution of aluminum chloride (175 mg, 1.31 mmol) in THF (4mL) at 0° C. was added sodium azide (170 mg, 2.61 mmol) then nitrile(5c) (133 mg, 0.38 mmol). The mixture was stirred 10 min and was heatedto reflux. After refluxing 5 h the mixture was diluted with 1N HCl, andwas extracted with EtOAc. The combined organic layers were washed withwater and dried (MgSO₄). The solvent was removed under reduced pressureand the residue was chromatographed (silica gel, 10-20% methanol/CH₂Cl₂)to give the tetrazole (5d, compound XIX, R³=H, R⁶=H as a white solid (84mg, 56%): ¹H NMR (CDCl₃) δ 7.49 (d, J=16.8 Hz, 1H),7.34-7.06 (m, 12H),6.91 (d, J=8.0 Hz, 2H), 6.79 (dd, J=7.3, 1.5 Hz, 1H), 2.84 (t, J=7.0 Hz,2H), 2.38 (t, J=7.0 Hz, 2H), 2.16 (m, 2H); ESI m/z: 389 (M−H⁻, 100%).

Example XXVIII Preparation ofN-{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-C,C,C-trifluoro-methanesulfonamide

[0210]

Procedure 1, Method B

[0211] Example 1e: To a solution of 1a (0.20 g, 0.564 mmol) in CH₂c1₂ (3mL) were added trifluoromethanesulfonamide (0.236 g, 1.58 mmol),4-dimethylaminopyridine (0.104 g, 0.851 mmol), and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.162 g,0.851 mmol). After stirring at room temperature for 24 hours,PS-Trisamine resin (0.600 mg) was added and stirring continued for onehour. The resin was collected by vacuum filtration and washed with 5%MeOH in CH₂Cl₂. The resin was treated with 5% TFA in CH₂Cl₂ (5 mL) andcollected by vacuum filtration. The filtrate was concentrated in vacuoto yield compound 1 as a pale yellow solid (0.041 mg, 15%): ¹H NMR(DMSO-d₆) δ 7.38-7.09 (m, 13H), 6.79 (d, J=8.4 Hz, 2H), 6.29 (d, J=15.8Hz, 1H), 2.35 (q, J=7.4 Hz), 0.82 (t, J=7.4 Hz, 3H); ApcI m/z=484.2(M−H⁻).

Example XXIX Preparation ofN-{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-2-nitro-benzenesulfonamide

[0212]

[0213] Example 1f: Prepared from the coupling of 1a and2-nitrobenzenesulfonamide by the method described in Procedure 1, MethodB. Yield (22%); ¹H NMR (d₆-DMSO) δ 8.18 (d, J=5.2 Hz, 1H), 7.99 (d,J=5.9 Hz, 1H), 7.94-7.84 (m, 2H), 7.44-7.08 (m, 13H), 6.86 (d, J=8.1 Hz,2H), 6.50 (d, J=15.7 Hz, 1H), 2.36 (q, J=7.4 Hz, 2H), 0.82 (t, J=7.4 Hz,3H); APcI m/z: 539 (M+H⁺).

Example XXX PreparationN-{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-3-nitro-benzenesulfonamide

[0214]

[0215] Example 1g: Prepared from the coupling of 1a and3-nitrobenzenesulfonamide by the method described in Procedure 1, MethodA. Yield (14%); ¹H NMR (d₆-DMSO) δ 8.59 (t, J=2.2 Hz, 1H), 8.47 (d,J=7.0 Hz, 1H), 8.30 (d, J=7.7 Hz, 1H) 7.87 (t, J=8.1 Hz, 1H), 7.38-7.07(m, 13H), 6.83 (d, J=8.4 Hz, 2H), 6.38 (d, J=15.7 Hz, 1H), 2.35 (q,J=7.4 Hz, 2H), 0.81 (t, J=7.4 Hz, 3H); APcI m/z: 537 (M−H⁻).

Example XXXI PreparationN-{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-4-nitro-benzenesulfonamide

[0216]

[0217] Example 1h: Prepared from the coupling of 1a and4-nitrobenzenesulfonamide by the method described in Procedure 1, MethodA. Yield (32%); ¹H NMR (d₆-DMSO) δ 8.33 (d, J=8.8 Hz, 2H), 8.08 (d,J=8.8 Hz, 2H), 7.38-7.07 (m, 13H), 6.82 (d, J=8.0 Hz, 2H), 6.35 (d,J=15.7 Hz, 1H), 2.35 (q, J=7.3 Hz, 2H), 0.81 (t, J=7.3 Hz, 3H); APcIm/z: 538 (M).

Example XXXII Preparation ofN-{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-2-trifluoromethyl-benzenesulfonamide

[0218]

[0219] Example 1i: Prepared from the coupling of 1a and2-(trifluoromethyl)benzenesulfonamide (Synlett, 1997, 375) by the methoddescribed in Procedure 1, Method B. Yield (14%); ¹H NMR (d₆-DMSO) δ12.49 (br s, 1H), 7.98-7.90 (m, 3H), 7.39-7.08 (m, 13H), 6.85 (d, J=8.0Hz, 2H), 6.47 (d, J=15.7 Hz, 1H), 2.36 (q, J=7.3 Hz, 2H), 0.82 (t, J=7.3Hz, 3H); APcI m/z: 562 (M+H⁺)

Example XXXIII Preparation ofN-{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-3-trifluoromethyl-benzenesulfonamide

[0220]

[0221] Example 1j: Prepared from the coupling of 1a and3-(trifluoromethyl)benzenesulfonamide (Synlett, 1997, 375) by the methoddescribed in Procedure 1, Method B. Yield (35%); ¹H NMR (d₆-DMSO) δ8.22-8.08 (m, 3H), 7.86 (t, J=7.7 Hz, 1H), 7.42-7.07 (m, 13H), 6.84 (d,J=8.0 Hz, 2H), 6.40 (d, J=15.7 ′ Hz, 1H), 2.35 (q, J=7.3 Hz, 2H), 0.82(t, J=7.3 Hz, 3H); APcI m/z: 562 (M+H⁺).

Example XXXIV Preparation ofN-{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-4-trifluoromethyl-benzenesulfonamide

[0222]

[0223] Example 1k: Prepared from the coupling of 1a and4-(trifluoromethyl)benzenesulfonamide (Synlett, 1997, 375) by the methoddescribed in Procedure 1, Method B. Yield (18%); ¹H NMR (d₆-DMSO) δ12.46 (br s, 1H), 8.11 (d, J=8.5 Hz, 2H), 7.99 (d, J=8.5 Hz, 2H),7.40-7.07 (m, 13H), 6.84 (d, J=8.1 Hz, 2H), 6.40 (d, J=15.7 Hz, 1H),2.35 (q, J=7.3 Hz, 2H), 0.81 (t, J=7.3 Hz, 3H); APcI m/z: 562 (M+H⁺)

Example XXXV Preparation of4-cyano-N-{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-benzenesulfonamide

[0224]

[0225] Example 1l: Prepared from the coupling of 1a and4-cyanobenzenesulfonamide by the method described in Procedure 1, MethodB. Yield (21%); ¹H NMR (d6-DMSO) δ 8.09-8.03 (m, 4H), 7.94 (d, J=8.0 Hz,1H), 7.40-7.07 (m, 12H), 6.84 (d, J=8.0 Hz, 2H), 6.40 (d, J=15.7 Hz,1H), 2.35 (q, J=7.4 Hz, 2H), 0.82 (t, J=7.4 Hz, 3H); APcI m/z: 519(M+H⁺)

Example XXXVI Preparation of2-chloro-N-{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-benzenesulfonamide

[0226]

[0227] Example 1m: Prepared from the coupling of 1a and2-chlorobenzenesulfonamide by the method described in Procedure 1,Method B. Yield (19%); ¹H NMR (d₆-DMSO) δ 12.56 (s, 1H), 8.09 (d, J=7.7Hz, 1H), 7.69-7.53 (m, 3H), 7.39-7.08 (m, 13H), 6.85 (d, J=8.1 Hz, 2H),6.47 (d, J=15.8 Hz, 1H), 2.36 (q, J=7.3 Hz, 2H), 0.82 (t, J=7.3 Hz, 3H);APcI m/z: 528 (M+H⁺)

Example XXXVII Preparation of3-chloro-N-{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-benzenesulfonamide

[0228]

[0229] Example 1n: Prepared from the coupling of 1a and3-chlorobenzenesulfonamide by the method described in Procedure 1,Method B. Yield (25%); ¹H NMR (d₆-DMSO) δ 12.36 (s, 1H), 7.88-7.76 (m,3H), 7.63 (t, J=8.1 Hz, 1H), 7.42-7.07 (m, 13H), 6.84 (d, J=8.0 Hz, 2H),6.40 (d, J=15.7 Hz, 1H), 2.36 (q, J=7.3 Hz, 2H), 0.82 (t, J=7.3 Hz, 3H);APcI m/z: 527 (M−H⁻)

Example XXXVIII Preparation of4-chloro-N-{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-benzenesulfonamide

[0230]

[0231] Example 1o: Prepared from the coupling of 1a and4-chlorobenzenesulfonamide by the method described in Procedure 1,Method B. Yield (22%); ¹H NMR (d₆-DMSO) δ 12.31 (br s, 1H), 7.90 (d,J=8.4 Hz, 2H), 7.66 (d, J=8.4 Hz, 2H), 7.39-7.07 (m, 13H), 6.84 (d,J=8.0 Hz, 2H), 6.40 (d, J=15.7 Hz, 1H), 2.35 (q, J=7.4 Hz, 2H), 0.82 (t,J=7.4 Hz, 3H); APcI m/z: 527 (M−H⁻).

Example XXXIX Preparation ofN-{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-2-methyl-benzenesulfonamide

[0232]

[0233] Example 1p: Prepared from the coupling of 1a and.-toluenesulfonamide by the method described in Procedure 1, Method B.Yield (37%); ¹H NMR (CD₃OD) δ 11.63 (br s, 1H), 7.54 (d, J=15.7 Hz, 2H),7.39-7.09 (m, 15H), 6.87 (d, J=8.0 Hz, 2H), 6.81 (s, 1H), 6.41 (d,J=15.7 Hz, 1H), 3.02-2.73 (s, 3H), 2.37 (q, J=7.3 Hz, 2H), 0.83 (t,J=7.3 Hz, 3H); APcI m/z: 508 (M+H⁺).

Example XL Preparation ofN-{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-3-methyl-benzenesulfonamide

[0234]

[0235] Example 1q: Prepared from the coupling of 1a andm-toluenesulfonamide (Synlett, 1997, 375) by the method described inProcedure 1, Method B. Yield (24%); ¹H NMR (CDCl) δ 7.86 (m, 2H), 7.50(d, J=15.7 Hz, 1H), 7.42-7.07 (m, 14H), 6.86 (d, J=8.4 Hz, 2H), 6.27 (d,J=15.7 Hz, 1H), 2.47 (q, J=7.3 Hz, 2H), 2.41 (s, 3H), 0.93 (t, J=7.3 Hz,3H); APcI m/z: 508 (M+H⁺).

Example XLI Preparation ofN-{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-4-methyl-benzenesulfonamide

[0236]

[0237] Example 1r: Prepared from the coupling of 1a andp-toluenesulfonamide by the method described in Procedure 1, Method B.Yield (42%); ¹H NMR (CD₃OD) δ 7.87 (d, J=8.2 Hz, 2H), 7.37-7.08 (m,15H), 6.87 (d, J=8.2 Hz, 2H), 6.32 (d, J=15.7 Hz, 1H), 2.44 (q, J=7.4Hz, 2H), 2.40 (s, 3H), 0.89 (t, J=7.3 Hz, 3H); APcI m/z: 508 (M+H⁺).

Example XLII Preparation of4-{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloylsulfamoyl}-benzoicAcid Methyl Ester

[0238]

[0239] Example 1s: Prepared from the coupling of 1a andp-carboxybenzenesulfonamide methyl ester (Synlett, 1997, 375) by themethod described in Procedure 1, Method B. Yield (25%); ¹H NMR (d₆-DMSO)δ 8.13 (d, J=8.8 Hz, 2H), 8.03 (d, J=8.8 Hz, 2H), 7.39-7.07 (m, 13H),6.84 (d, J=8.4 Hz, 2H), 6.40 (d, J=15.7 Hz, 1H), 3.86 (s, 3H), 2.36 (q,J=7.3 Hz, 2H), 2.41 (s, 3H), 0.82 (t, J=7.3 Hz, 3H); APcI m/z: 552(M+H⁺)

Example XLIII Preparation ofN-{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-4-methoxy-benzenesulfonamide

[0240]

[0241] Example 1t: Prepared from the coupling of 1a and4-methoxybenzenesulfonamide by the method described in Procedure 1,Method B. Yield (24%); ¹H NMR (d₆-DMSO) δ 12.04 (br s, 1H), 7.83 (d,J=8.8 Hz, 2H), 7.38-7.07 (m, 15H), 6.84 (d, J=8.0 Hz, 2H), 6.39 (d,J=15.7 Hz, 1H), 3.80 (s, 3H), 2.35 (q, J=7.3 Hz, 2H), 0.82 (t, J=7.3 Hz,3H); APcI m/z: 525 (M+H⁺)

Example XLIV Preparation ofN-{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-3-methoxy-benzenesulfonamide

[0242]

[0243] Example 1u: Prepared from the coupling of 1a and3-methoxybenzenesulfonamide (Synlett, 1997, 375) by the method describedin Procedure 1, Method B. Yield (27%); ¹H NMR (d₆-DMSO) δ 12.18 (br s,1H), 7.53-7.07 (m, 17H), 6.84 (d, J=8.0 Hz, 2H), 6.40 (d, J=15.7 Hz,1H), 3.78 (s, 3H), 2.35 (q, J=7.4 Hz, 2H), 0.82 (t, J=7.4 Hz, 3H); APcIm/z: 522 (M−H⁻)

Example XLV Preparation ofN-{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-4-hydroxy-benzenesulfonamide

[0244]

[0245] Example 1v: Prepared from 1t by treating with boron tribromide (3eq) in CH₂Cl₂ at room temperature. Yield (29%); ¹H NMR (d6-DMSO) δ 11.95(br s, 1H), 10.57 (s, 1H), 7.71 (d, J=8.8 Hz, 2H), 7.38-7.07 (m, 13H),6.85 (t, J=8.8 Hz, 4H), 6.38 (d, J=15.7 Hz, 1H), 2.36 (q, J=7.4 Hz, 2H),0.82 (t, J=7.4 Hz, 3H); APcI m/z: 510 (M+H⁺)

Example XLVI Preparation ofN-{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-3-hydroxy-benzenesulfonamide

[0246]

[0247] Example 1w: Prepared from 1u by treating with boron tribromide (3eq) in CH₂Cl₂ at room temperature. Yield (57%); ¹H NMR (d₆-DMSO) δ 12.15(br s, 1H), 10.19 (s, 1H), 7.41-7.02 (m, 17H), 6.86 (d, J=8.0 Hz, 2H),6.42 (d, J=15.7 Hz, 1H), 2.37 (q, J=7.4 Hz, 2H), 0.83 (t, J=7.4 Hz, 3H);APcI m/z: 510 (M+H⁺)

Example XLVII Preparation of 3-chloro-propane-1-sulfonic Acid{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-amide

[0248]

[0249] Example 1x: Prepared from the coupling of 1a and3-chloropropanesulfonamide (Synlett, 1997, 375) by the method describedin Procedure 1, Method A. Yield (80%); ¹H NMR (d₆-DMSO) δ 11.82 (br s,1H), 7.48 (d, J=15.7 Hz, 1H), 7.40-7.09 (m, 12H), 6.87 (d, J=8.4 Hz,2H), 6.46 (d, J=15.7 Hz, 1H), 3.71 (t, 2H), 3.52 (t, 2H), 2.37 (q, J=7.3Hz, 2H), 2.07 (p, 2H), 0.83 (t, J=7.3 Hz, 3H); APcI m/z: 492 (M−H⁻)

Example XLVIII Preparation of(4-{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloylsulfamoyl}-phenyl)-carbamicAcid Tert-Butyl Ester

[0250]

[0251] Example 1y: Prepared from the coupling of 1a and 4-BOCsulfanilamide (Heterocycles, 1996, 2741; Synlett, 1997, 375) by themethod described in Procedure 1, Method A. Yield (67%); ¹H NMR (d₆-DMSO)δ 12.02 (br s, 1H), 9.86 (s, 1H), 7.78 (d, J=8.8 Hz, 2H), 7.60 (d, J=8.8Hz, 2H), 7.38-7.08 (m, 13H), 6.83 (d, J=8.4 Hz, 2H), 6.38 (d, J=15.7 Hz,1H), 2.36 (q, J=7.3 Hz, 2H), 1.44 (s, 9H), 0.82 (t, J=7.3 Hz, 3H); APcIm/z: 607 (M−H⁻)

Example XLIX Preparation of 3-Piperidin-1-yl-propane-1-sulfonic Acid{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-amide

[0252]

[0253] Example 1z: Prepared from the coupling of 1x and piperidine (15eq) in tetrahydrofuran at reflux. The product precipitated from amixture of ethyl acetate and 1N HCl as the HCl salt. Yield (60%); ¹H NMR(d₆-DMSO) δ 11.90 (br s, 1H), 7.47 (d, J=15.7 Hz, 1H), 7.40-7.09 (m,12H), 6.87 (d, J=7.7 Hz, 2H), 6.53 (d, J=15.7 Hz, 1H), 3.08 (br, 2H),2.95 (br, 1H), 2.81 (br, 2H), 2.37 (q, J=7.3 Hz, 2H), 2.08 (br, 2H),1.71 (br, 6H), 1.62 (br, 1H), 0.83 (t, J=7.3 Hz, 3H); APcI m/z: 541(M−H⁻).

Example L Preparation of4-amino-N-{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-benzenesulfonamide

[0254]

[0255] Example 1aa: Prepared from the treatment of 1y withtrifluoroacetic acid (50% in CH₂Cl₂). Yield (92%); ¹H NMR (d₆-DMSO) δ11.71 (br s, 1H), 7.51 (d, J=8.7 Hz, 2H), 7.38-7.07 (m, 13H), 6.83 (d,J=8.1 Hz, 2H), 6.55 (d, J=8.7 Hz, 2H), 6.37 (d, J=15.7 Hz, 1H), 2.35 (q,J=7.4 Hz, 2H), 1.44 (s, 9H), 0.82 (t, J=7.3 Hz, 3H); APcI m/z: 507(M−H⁻).

Example LI Preparation of Ethanesulfonic Acid{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-amide

[0256]

[0257] Example 1y: Prepared from the coupling of 1a andethanesulfonamide (Synlett, 1997, 375) by the method described inProcedure 1, Method B. Yield (25%); ¹H NMR (d₆-DMSO) δ 11.67 (br s, 1H),7.47 (d, J=15.7 Hz, 1H), 7.40-7.09 (m, 12H), 6.86 (d, J=8.4 Hz, 2H),6.47 (d, J=15.7 Hz, 1H), 3.37 (q, J=7.4 Hz, 2H), 2.36 (q, J=7.3 Hz, 2H),1.16 (t, J=7.3 Hz, 3H), 0.83 (t, J=7.3 Hz, 3H); APcI m/z: 444 (M−H⁻).

Example LII Preparation of4-{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloylsulfamoyl}-N,N-dimethyl-benzamide

[0258]

[0259] Example 1cc: Prepared from the coupling of 1aa withN,N-dimethylglycine (2.8 eq) using 4-dimethylaminopyridine (1.5 eq) and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.5 eq)in CH₂Cl₂ at room temperature. The product was isolated as thehydrochloride salt. Yield (28%); ¹H NMR (d₆-DMSO) δ 10.26 (br s, 1H),7.76 (q, J=8.5 Hz, 4H), 7.38-7.08 (m, 13H), 6.81 (d, J=8.1 Hz, 2H), 6.34(d, J=15.7 Hz, 1H), 3.35 (br s, 2H), 2.39-2.35 (m, 8H), 0.82 (t, J=7.3Hz, 3H); APcI m/z: 594 (M+H⁺).

Example LIII Preparation of propane-2-sulfonic acid{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-amide

[0260]

[0261] Example 1dd: Prepared from the coupling of 1a andisopropylsulfonamide (Synlett, 1997, 375) by the method described inProcedure 1, Method B. Yield (13%); ¹H NMR (d₆-DMSO) δ 11.60 (br s, 1H),7.46 (d, J=15.7 Hz, 1H), 7.40-7.09 (m, 12H), 6.86 (d, J=8.1 Hz, 2H),6.48 (d, J=15.7 Hz, 1H), 3.64 (m, 1H), 2.37 (q, J=7.3 Hz, 2H), 1.23 (d,J=7.0 Hz, 6H), 0.83 (t, J=7.3 Hz, 3H); APcI m/z: 460 (M+H⁺).

Example LIV Preparation of propane-2-sulfonic acid{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-amide

[0262]

[0263] Example 1ee: Prepared from the coupling of 1a and[(4-fluorophenyl)methyl]sulfonamide (Synlett, 1997, 375) by the methoddescribed in Procedure 1, Method B. Yield (32%); ¹H NMR (d₆-DMSO) δ11.63 (br s, 1H), 7.53 (d, J=15.7 Hz, 1H), 7.40-7.10 (m, 16H), 6.87 (d,J=8.1 Hz, 2H), 6.41 (d, J=15.7 Hz, 1H), 4.72 (s, 2H), 2.37 (q, J=7.4 Hz,2H), 0.83 (t, J=7.4 Hz, 3H); APcI m/z: 526 (M+H⁺).

Example LV Preparation of4-{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloylsulfamoyl}-benzoicAcid

[0264]

[0265] Example 1ff: Prepared from the hydrolysis of 1s using 4N aqsodium hydroxide (2 eq) in 4:1 dioxane/methanol at room temperature.Yield (82%); ¹H NMR (d6-DMSO) δ 13.48 (br s, 1H), 12.36 (br s, 1H), 8.10(d, J=8.0 Hz, 2H), 8.02 (d, J=8.0 Hz, 2H), 7.39-7.07 (m, 13H), 6.84 (d,J=8.1 Hz, 2H), 6.41 (d, J=15.7 Hz, 1H), 2.35 (q, J=7.7 Hz, 2H), 0.82 (t,J=7.7 Hz, 3H); APcI m/z: 538 (M+H⁺)

Example LVI Preparation ofN-(4-{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloylsulfamoyl}-phenyl)-acetamide

[0266]

[0267] Example 1gg: Prepared by the acylation of 1aa with acetylchloride (1.3 eq) in refluxing tetrahydrofuran using triethylamine (2.6eq) as base. Yield (81%); ¹H NMR (d₆-DMSO) δ 12.06 (br s, 1H), 10.35 (brs, 1H), 7.82 (d, J=9.0 Hz, 2H), 7.73 (d, J=9.0 Hz, 2H), 7.38-7.07 (m,13H), 6.84 (d, J=8.1 Hz, 2H), 6.39 (d, J=15.7 Hz, 1H), 2.35 (q, J=7.4Hz, 2H), 2.04 (s, 3H), 0.82 (t, J=7.4 Hz, 3H); APcI m/z: 551 (M+H⁺)

Example LVII Preparation of 2,2,2-trifluoro-ethanesulfonic Acid{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-amide

[0268]

[0269] Example 1hh: Prepared from the coupling of 1a and2,2,2-trifluoroethanesulfonamide (Synlett, 1997, 375) by the methoddescribed in Procedure 1, Method A. Yield (34%); ¹H NMR (d₆-DMSO) δ7.39-7.01 (m, 13H), 6.83 (d, J=8.1 Hz, 2H), 6.40 (d, J=15.7 Hz, 1H),2.85 (s, 1H), 2.69 (s, 1H), 2.36 (q, J=7.3 Hz, 2H), 0.83 (t, J=7.3 Hz,3H); ESI m/z: 498 (M−H⁻).

Example LVIII Preparation of thiophene-2-sulfonic Acid{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-amide

[0270]

[0271] Example 1ii: Prepared from the coupling of 1a and2-thiophenesulfonamide (Synlett, 1997, 375) by the method described inProcedure 1, Method A. Yield (27%); ¹H NMR (d₆-DMSO) δ 12.34 (br s, 1H),7.99 (m, 1H), 7.76 (m, 1H), 7.39-7.08 (m, 14H), 6.85 (d, J=8.4 Hz, 2H),6.41 (d, J=15.7 Hz, 1H), 2.36 (q, J=7.3 Hz, 2H), 0.82 (t, J=7.3 Hz, 3H);APcI m/z: 500 (M+H⁺)

Example LIX Preparation ofN-{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-C-(4-trifluoromethyl-phenyl)-methanesulfonamide

[0272]

[0273] Example 1jj: Prepared from the coupling of 1a and[(4-trifluoromethylphenyl)methyl]sulfonamide (Synlett, 1997, 375) by themethod described in Procedure 1, Method B. Yield (11%); ¹H NMR (d₆-DMSO)δ 11.69 (br s, 1H), 7.74 (d, J=8.0 Hz, 2H), 7.57-7.09 (m, 15H), 6.87 (d,J=8.1 Hz, 2H), 6.41 (d, J=15.7 Hz, 1H), 4.86 (s, 2H), 2.37 (q, J=7.3 Hz,2H), 0.83 (t, J=7.3 Hz, 3H); APcI m/z: 576 (M+H⁺).

Example LX Preparation of4-{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloylsulfamoyl}-N-methyl-benzamide

[0274]

[0275] Example 1kk: Prepared from the coupling of 1ff and methylaminehydrochloride (2.5 eq) in the presence of BOP reagent (2.2 eq) and4-methylmorpholine (1.5 eq) using N,N-dimethylformamide as solvent.Yield (32%); ¹H NMR (d₆-DMSO) δ 13.48 (br s, 1H), 8.63 (q, J=4.4 Hz,1H), 7.96 (s, 4H), 7.37-7.07 (m, 13H), 6.84 (d, J=8.4 Hz, 2H), 6.40 (d,J=15.7 Hz, 1H), 2.75 (d, J=4.4 Hz, 3H), 2.35 (q, J=7.7 Hz, 2H), 0.84 (t,J=7.7 Hz, 3H); APcI m/z: 549 (M−H⁻).

Example LXI Preparation of benzothiazole-2-sulfonic acid{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-amide

[0276]

[0277] Example 1ll: Prepared from the coupling of 1a and2-benzothiazolesulfonamide (J Org Chem, 1958, 1768) by the methoddescribed in Procedure 1, Method A. Yield (52%); ¹H NMR (d₆-DMSO) δ 8.07(d, J=8.3 Hz, 1H), 7.99 (d, J=8.3 Hz, 1H), 7.53-7.05 (m, 15H), 6.78 (d,J=8.1 Hz, 2H), 6.27 (d, J=15.7 Hz, 1H), 2.35 (q, J=7.3 Hz, 2H), 0.82 (t,J=7.3 Hz, 3H); APcI m/z: 551 (M+H⁺).

Example LXII Preparation of 3-chloro-propane-1-sulfonic Acid{3-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenyl]-acryloyl}-amide

[0278]

[0279] Example 2i: Prepared from the coupling of 2e and3-chloropropanesulfonamide by the method described in Procedure 1,Method A. Yield (65%); ¹H NMR (d₆-DMSO) δ 11.83 (s, 1H), 7.54 (d, J=15.7Hz, 1H), 7.34-7.09 (m, 10H), 6.87 (d, J=8.1 Hz, 2H), 6.70 (d, J=7.3 Hz,1H), 6.51 (d, J=15.7 Hz, 1H), 3.72 (t, J=6.4 Hz, 2H), 3.54 (t, J=6.4 Hz,2H), 2.77 (t, J=7.0 Hz, 2H), 2.26 (t, J=7.0 Hz, 2H), 2.08 (m, 4H); APcIm/z: 504 (M−H⁻).

Example LXIII Preparation ofC,C,C-trifluoro-N-{3-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenyl]-acryloyl}-methanesulfonamide

[0280]

[0281] Example 2j: Prepared from the coupling of 2e andtrifluoromethanesulfonamide by the method described in Procedure 1,Method B. Yield (12%); ¹H NMR (d₆-DMSO) δ 8.93 (br s, 2H), 7.31-7.07 (m,9H), 6.80 (d, J=8.0 Hz, 2H), 6.72 (d, J=7.3 Hz, 1H), 6.35 (d, J=15.7 Hz,1H), 2.76 (t, J=7.0 Hz, 2H), 2.26 (t, J=7.0 Hz, 2H), 2.07 (m, 2H); APcIm/z: 496 (M−H⁻).

Example LXIV Preparation of 3-piperidin-1-yl-propane-1-sulfonic Acid{3-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenyl]-acryloyl}-amide

[0282]

[0283] Example 2k: Prepared from the coupling of 2i and piperidine (15eq) in tetrahydrofuran at reflux. The product was isolated as thehydrochloride salt. Yield (70%); ¹H NMR (d₆-DMSO) δ 11.90 (br s, 1H),7.53 (d, J=15.7 Hz, 1H), 7.34-7.10 (m, 12H), 6.88 (d, J=8.4 Hz, 2H),6.70 (d, J=7.3 Hz, 1H), 6.55 (d, J=15.7 Hz, 1H), 3.52 (t, J=7.3 Hz, 2H),3.09 (br, 2H), 2.77 (br m, 4H), 2.26 (br t, 2H), 2.08 (br, 4H), 1.71(br, 5H); APcI m/z: 555 (M+H⁺).

Example LXV Preparation ofC-(4-fluoro-phenyl)-N-{3-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenyl]-acryloyl}-methanesulfonamide

[0284]

[0285] Prepared from the coupling of 2e and4-(fluorophenyl)methylsulfonamide (Synlett, 1997, 375) by the methoddescribed in Procedure 1, Method A. Yield (61%); ¹H NMR (d₆-DMSO) δ11.64 (br s, 1H), 7.58 (d, J=15.7 Hz, 1H), 7.33-7.11 (m, 14H), 6.88 (d,J=8.0 Hz, 2H), 6.70 (d, J=7.3 Hz, 1H), 6.45 (d, J=15.7 Hz, 1H), 4.72 (s,2H), 2.77 (t, J=6.4 Hz, 2H), 2.26 (t, J=6.4 Hz, 2H), 2.08 (t, J=6.4 Hz,2H); APcI m/z: 538 (M+H⁺)

Example LXVI Preparation of4-(6-Methoxy-2-phenyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-phenol

[0286]

[0287] Compound 6a is prepared according to the method described onpages 172-176 of Volume 9 J. Med. Chem 1966. A suspension of4-(4-hydroxyphenyl)-7-methoxy-3-phenyl-1,2-dihydronaphthalene 6a (829mg, 2.52 mmol) and 20% Pd(OH)₂/C (500 mg) in ethanol (100 mL) wasstirred 2 days under an atmosphere of hydrogen. The mixture was filteredthrough Celite and the solvent was removed under reduced pressure togive the cis-tetrahydronaphtahalene 6b as a white solid (834 mg, 100%):ESI m/z: 329 (M−H⁻).

Example LXVII Preparation of Trifluoro-methanesulfonic acid4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-phenyl Ester

[0288]

[0289] Prepared from the tetrahydronaphtahalene 6b by the general methoddescribed for example 3b. Yield (81%); ¹⁹F NMR (CDCl₃) δ −73.21.

Example LXVIII Preparation of3-[4-(6-Methoxy-2-phenyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-phenyl]-acrylicAcid Methyl Ester

[0290]

[0291] Prepared from the Heck coupling of 6c and methyl acrylate by thegeneral method described for example 2b. Yield (83%); APcI m/z: 440(M+H+CH₃CN⁺, 100%).

Example LXIX Preparation of3-[4-(6-Methoxy-2-phenyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-phenyl]-acrylicAcid

[0292]

[0293] Prepared from the saponification (hydrolysis) of ester 6d by thegeneral method described for example 2e. Yield (93%); APcI m/z: 426(M+H+CH₃CN⁺, 100%).

Example LXIX Preparation of3-[4-(6-Hydroxy-2-phenyl-1,2,3,4-tetrahydro-naphthalen-lyl)-phenyl]-acrylicAcid

[0294]

[0295] To a solution of the ether 6e (120 mg, 0.312 mmol) in CH₂Cl₂ (12mL) at 0° C. was added 1M boron tribromide in CH₂Cl₂ (4 mL). The mixturewas stirred 1.5 h at room temperature and was quenched with ice/H₂O.After stirring 2 h, the mixture was extracted with CH₂Cl₂. The combinedorganic layers were washed with water and dried (MgSO₄). The solvent wasremoved under reduced pressure and the residue was chromatographed(silica gel, 10-20% methanol/CH₂Cl₂) to give the phenol 6f as a whitesolid (45 mg, 39%): ESI m/z: 369 (M−H⁻, 100%).

Example LXX Resolution of3-[4-(6-Hydroxy-2-phenyl-1,2,3,4-tetrahydro-naphthalen-1yl)-phenyl]-acrylicAcid

[0296]

[0297] Resolution of 6f of Example LXIX: The 2 enantiomers 6g and 6hwere isolated by a preparative chiral HPLC of 6f. (Chiralcel OD column,trifluoroacetic acid/CH₃CN::1/1000 elutant)

Example LXX Preparation of Trifluoro-methanesulfonic acid4-(2-phenyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-phenyl Ester

[0298]

[0299] Compound 7a is prepared according to the procedure set forth onpages 138-144 of Volume 10 J. Med. Chem 1967. Compound 7b is thenprepared from 4-(2-phenyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-phenol(7a) by the general method described for example 3b. Yield (95%); ¹H NMR(CDCl₃) δ 7.28-6.75 (m, 1H), 6.48 (d, J=8.4 Hz, 2H), 4.36 (d, J=5.4 Hz,1H), 3.44 (m, 1H), 3.11 (m, 2H), 2.12 (m, 1H), 1.90 (m, 1H).

Example LXXI Preparation of3-[4-(2-Phenyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-phenyl]-acrylic AcidMethyl Ester

[0300]

[0301] Prepared from the Heck coupling of 7b and methyl acrylate by thegeneral method described for example 2b. Yield (76%); APcI m/z: 410(M+H+CH₃CN⁺, 100%).

Example LXXI Preparation of3-[4-(2-Phenyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-phenyl]-acrylic Acid

[0302]

[0303] Prepared from the saponification (hydrolysis) of ester 7c by thegeneral method described for example 2e. Yield (86%); ESI m/z: 353(M−H⁻, 100%).

Example LXXI Preparation ofN-{3-[4-(2-Phenyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-phenyl]-acryloyl}-methanesulfonamide

[0304]

[0305] Prepared from the coupling of 7d and methylsulfonamide by themethod described in Procedure 1, Method A. Yield (56%); ¹H NMR (CDCl) δ7.63 (d, J=15.4 Hz, 1H), 7.14 (m, 8H), 6.83 (m, 3H), 6.46 (d, J=8.1 Hz,2H), 6.26 (d, J=15.4 Hz, 1H), 4.37 (d, J=5.1 Hz, 1H), 3.46 (m, 1H), 3.34(s, 3H), 3.13 (m, 2H), 2.16 (m, 1H), 1.88 (m, 1H); ESI m/z: 430 (M−H⁻,100%).

Example LXXII Preparation ofN-{3-[4-(2-Phenyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-phenyl]-acryloyl}-benzenesulfonamide

[0306]

[0307] Prepared from the coupling of 7d and benzene sulfonamide by themethod described in Procedure 1, Method A. ESI m/z: 492 (M−H⁻, 100%).

Example LXXIII Preparation of4-(6-Phenyl-6,7,8,9-tetrahydro-5H-benzocyclohepen-5-yl)-phenol

[0308]

[0309] Compound 8a is prepared according to the synthesis shown at pages2053-2059 of Volume 29 of the J. Med. Chem 1986. Prepared from6,7-dihydro-8-phenyl-9-(4-hydroxyphenyl)-5H-benzocycloheptene (8a) bythe general method described for example 6b. Yield (91%); ¹H NMR (CDCl₃)δ 7.29-6.98 (m, 9H), 6.63 (m, 4H), 4.63 (d, J=1.5 Hz, 1H), 3.49 (m, 1H),3.00 (m, 2H), 2.07 (m, 3H), 1.75 (m, 1H).

Example LXXIV Preparation of Triflouro-methanesulfonic Acid4-(6-phenyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl)-phenyl Ester

[0310]

[0311] Prepared from 8b by the general method described for example 3b.Yield (89%); ¹H NMR (CDCl₃) δ 7.31-6.84 (m, 13H), 4.70 (br s, 1H), 3.53(br d, J=9.5 Hz, 1H), 2.98 (m, 2H), 2.17 (m, 1H), 2.00 (m, 2H), 1.75 (m,1H).

Example LXXV Preparation of3-[4-{6-Phenyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl)-phenyl]-acrylicAcid Methyl Ester

[0312]

[0313] Prepared from the Heck coupling of 8c and methyl acrylate by thegeneral method described for example 2b. Yield (14%); APcI m/z: 424(M+H+CH₃CN⁺, 100%)

Example LXXVI Preparation of3-[4-{6-Phenyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl)-phenyl]-acrylic Acid

[0314]

[0315] Prepared from the saponification (hydrolysis) of ester 8d by thegeneral method described for example 2e. Yield (30%); ESI m/z: 367(M−H⁻, 100%).

[0316] All aforementioned patent applications, patents and otherpublications are herein incorporated by reference in their entirity asthough set forth in full.

What is claimed is:
 1. A compound of Formula (I):

or pharmaceutically acceptable salt form thereof, wherein R¹ is selectedfrom the group consisting of

R² is selected from the group consisting of H, C₁₋₈ alkyl and halo; R³is selected from the group consisting of H, C₁₋₈ alkyl, C₁₋₈ alkylenyl,halo, or CN; alternatively R² and R³, together with the atoms to whichthey are attached, form a six- or seven-membered ring structure whereone or more of the atoms forming the ring may be oxygen; R⁴ is selectedfrom the group consisting of H, OH, C₁₋₈ alkyl, OC₁₋₈ alkyl and halo; R⁵is selected from the group consisting of H, OH, CN, nitro, C₁₋₈ alkyl,OC₁₋₈ alkyl and halo; R⁶ is selected from the group of H, OH, CN, OC₁₋₈alkyl methyl, ethyl, propyl and butyl; R⁷ is selected from the groupconsisting of H, aryl, C₁₋₈ alkyl, OH, and OC₁₋₈ alkyl; R⁸ is selectedfrom the group consisting of aryl, C₁₋₈ alkyl, OH, and OC₁₋₈ alkyl,wherein said R⁸ is optionally substituted with 1 to 2 substituentsselected from halo, nitro, OH, CN, C₁₋₄ alkyl, OC₁₋₄ alkyl, NH₂, andNHC(O)OC(CH₃)₃; X is selected from the group consisting of O or NH,wherein when X is O, R⁶ is other than OH; and, the broken linerepresents an optional double bond.
 2. A compound according to claim 1wherein R¹ is


3. A compound according to claim 1 wherein R¹ is


4. A compound according to claim 1 wherein R¹ is


5. A compound according to claim 1 wherein R¹ is


6. A compound according to claim 1 wherein R² and R³ together with theatoms to which they are attached form a seven-membered ring.
 7. Acompound according to claim 1 wherein R² and R³ together with the atomsto which they are attached form a six membered ring.
 8. A compoundaccording to claim 1 wherein R is CH₃.
 9. A compound according to claim1 wherein R is CN.
 10. A compound according to claim 1 wherein R³ isCH═CH₂.
 11. A compound according to claim 1 wherein R is H.
 12. Acompound according to claim 1 selected from the group consisting of: b)3-{4-[6-(3-Methoxy-phenyl)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenyl}-acrylicacid; b) 3-{4-[6-(4-Methoxy-phenyl)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenyl}-acrylic acid; c)3-{4-[6-(3-Hydroxy-phenyl)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenyl}-acrylicacid; d)3-{4-[6-(4-Hydroxy-phenyl)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenyl}-acrylicacid; e) 5-{2-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-vinyl}-1H-tetrazole;f)3-[4-(6-Phenyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl)-phenyl]-acrylicacid; g)3-[4-(2-Hydroxy-6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenyl]-acrylicacid; h)3-{4-[2-Hydroxy-6-(3-hydroxy-phenyl)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenyl}-acrylicacid; i)3-{4-[2-Hydroxy-6-(4-hydroxy-phenyl)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenyl}-acrylicacid; j)5-{2-[4-(6-Phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenyl]-vinyl}-1H-tetrazole;k)5-{2-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-vinyl}-1-methyl-1H-tetrazole;l)5-(2-{4-[6-(3-Methoxy-phenyl)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenyl}-vinyl)-1H-tetrazole;m) 3-[4-(6-Hydroxy-2-phenyl-3,4-dihydro-naphthalen-1-yl)-phenyl]-acrylicacid; n)3-[4-(6-Hydroxy-2-phenyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-phenyl]-acrylicacid; o)3-[4-(6-Phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenyl]-propionicacid; p)3-[4-(6-Hydroxy-2-phenyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-phenyl]-acrylicacid; q)3-[4-(6-Hydroxy-2-phenyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-phenyl]-acrylicacid; r) 3-[4-(3-Phenyl-2H-chromen-4-yl)-phenyl]-acrylic acid; s)3-[4-(2-Phenyl-3,4-dihydro-naphthalen-1-yl)-phenyl]-acrylic acid; t)3-[4-(2-Phenyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-phenyl]-acrylic acid;u) 3-[4-(6-Phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenyl]-acrylicacid; v)N-{3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acryloyl}-methanesulfonamide;w)N-{3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acryloyl}-benzenesulfonamide;x)N-{3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acryloyl}-C-phenyl-methanesulfonamide;y)N-{3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acryloyl}-3-nitro-benzenesulfonamide;z)N-{3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acryloyl}-4-nitro-benzenesulfonamide;aa)N-{3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acryloyl}-2-methyl-benzenesulfonamide;ab)N-{3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acryloyl}-4-methyl-benzenesulfonamide;ac)N-{3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acryloyl}-2-nitro-benzenesulfonamide;ad)N-{3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acryloyl}-C,C,C-trifluoro-methanesulfonamide;ae)N-{3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acryloyl}-4-methoxy-benzenesulfonamide;af)4-Chloro-N-{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-benzenesulfonamide;ag)4-Cyano-N-{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-benzenesulfonamide;ah)N-{3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acryloyl}-3-trifluoromethyl-benzenesulfonamide;ai)2-Chloro-N-{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-benzenesulfonamide;aj)3-Chloro-N-{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-benzenesulfonamide;ak)N-{3-[4-(2-Phenyl-3,4-dihydro-naphthalen-1-yl)-phenyl]-acryloyl}-methanesulfonamide;al)N-{3-[4-(2-Phenyl-3,4-dihydro-naphthalen-1-yl)-phenyl]-acryloyl}-benzenesulfonamide;am)N-{3-[4-(3-Phenyl-2H-chromen-4-yl)-phenyl]-acryloyl}-methanesulfonamide;an)N-{3-[4-(3-Phenyl-2H-chromen-4-yl)-phenyl]-acryloyl}-benzenesulfonamide;ao) 4-{3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acryloylsulfamoyl}-benzoicacid methyl ester; ap)N-{3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acryloyl}-2-trifluoromethyl-benzenesulfonamide;aq)N-{3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acryloyl}-3-methyl-benzenesulfonamide;ar)N-{3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acryloyl}-4-hydroxy-benzenesulfonamide;as)N-{3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acryloyl}-3-methoxy-benzenesulfonamide;at)N-{3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acryloyl}-4-trifluoromethyl-benzenesulfonamide;au)N-{3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acryloyl}-3-hydroxy-benzenesulfonamide;av) N-(2-Cyano-ethyl)-3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acrylamide;aw)N-{3-[4-(6-Phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenyl]-acryloyl}-methanesulfonamide;ax)N-{3-[4-(6-Phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenyl]-acryloyl}-benzenesulfonamide;ay)C-Phenyl-N-{3-[4-(2-phenyl-3,4-dihydro-naphthalen-1-yl)-phenyl]-acryloyl}-methanesulfonamide;az)C-Phenyl-N-{3-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenyl]-acryloyl}-methanesulfonamide;ba) 3-Chloro-propane-1-sulfonic acid{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-amide; bb)(4-{3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acryloylsulfamoyl}-phenyl)-carbamicacid tert-butyl ester; bc) 3-Piperidin-1-yl-propane-1-sulfonic acid{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-amide; bd)4-Amino-N-{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-benzenesulfonamide;be) Ethanesulfonic acid{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-amide; bf)2-Dimethylamino-N-(4-{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloylsulfamoyl}-phenyl)-acetamide;bg) Propane-2-sulfonic acid{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-amide; bh)N-{3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acryloyl}-C-(4-fluoro-phenyl)-methanesulfonamide;bi) 4-{3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acryloylsulfamoyl}-benzoicacid; bj)N-(4-{3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acryloylsulfamoyl}-phenyl)-acetamide;bk) 2,2,2-Trifluoro-ethanesulfonic acid{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-amide; bl)3-Chloro-propane-1-sulfonic acid{3-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenyl]-acryloyl}-amide;bm)C,C,C-Trifluoro-N-{3-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenyl]-acryloyl}-methanesulfonamide;bn) 3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-N-hydroxy-acrylamide; bo)3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-N-methoxy-acrylamide; bp)3-Piperidin-1-yl-propane-1-sulfonic acid{3-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenyl]-acryloyl}-amide;bq)C-(4-Fluoro-phenyl)-N-{3-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenyl]-acryloyl}-methanesulfonamide;br) Thiophene-2-sulfonic acid{3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acryloyl}-amide; bs)N-{3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acryloyl}-C-(4-trifluoromethyl-phenyl)-methanesulfonamide;and, bt)4-{3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acryloylsulfamoyl}-N-methyl-benzamide.13. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier in combination with a therapeutically effectiveamount of a compound of claim
 1. 14. A method of modulating the estrogenreceptor in a patient in need of said modulating comprising the steps ofadministering to said patient a therapeutically effective amount of acompound of claim
 1. 15. A method of treating breast, uterine, ovarian,prostate or colon cancer, osteoporosis, cardiovascular disease,endometriosis, uterine fibroid, Alzheimer's disease, maculardegeneration, urinary incontinence, type II diabetes, or benignproliferative disorders, comprising: administering to a host in need ofsuch treatment a therapeutically effective amount of a compound ofclaim
 1. 16. A compound of Formula (II):

wherein R¹ is selected from the group consisting of

R⁶ is selected from the group of H, methyl, ethyl, propyl and butyl; R⁷is selected from the group consisting of aryl and C₁₋₈ alkyl, optionallysubstituted with one or more substituent groups; and R⁸, R⁹, R¹⁰ and R¹¹are the same or different, and are independently selected from the groupconsisting of: H, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, aryl, NO₂,NH₂, OH, OC₁₋₈ alkyl, CHO, COOH, halo and CN, wherein said R⁸ isoptionally substituted with 1 to 2 substituents selected from halo,nitro, OH, CN, C₁₋₄ alkyl, OC₁₋₄ alkyl, NH₂, and NHC(O)OC(CH₃)₃.